This document provides information on type 1 diabetes mellitus (DM). It discusses that type 1 DM results from complete or near-total deficiency of insulin due to destruction of beta cells, which is usually the result of an autoimmune process involving genetic and environmental triggers. Over months to years, autoimmune destruction of beta cells gradually reduces beta cell mass until insulin secretion can no longer maintain normal glucose tolerance, resulting in overt diabetes.

1. Diabete Mellito
Liberamente tratto dall’Harrison 17th ed.

2. • Malattia endocrino metabolica
• L’ iperglicemia è l’attore protagonista
• Dialogo sbagliato sbagliato fra glucosio e insulina

3. Iperglicemia
• ridotta secrezione di insulina
• ridotto utilizzo di glucosio
• aumento nella produzione di glucosio

4. Alterazioni patofisiologiche
• Le alterazioni metaboliche associate a DM sono la
principale causa di:
• Grave nefropatia (end-stage renal disease ESRD)
• amputazione degli arti inferiore non ascrivibile a
trauma
• cecità in età adulta

5. Classificazione DM
• classificato in base in base al processo patogenetico
che determina l’iperglicemia

6. • Tipo I (5-10%): completa o quasi totale deficienza
di insulina, distruzione β-cells.
• Tipo II (~90-95%): gruppo eterogeneo di disordini
con vario grado di ridotta secrezione di insulina,
resistenza all’insulina e aumentata produzione di
glucosio

7. • Altri tipi di DM: difetti genetici o problemi
metabolici che coinvolgono azione e sintesi
dell’insulina, difetti mitocondriali, malattia
pankreas esocrino con distruzione isole, eccesso di
ormoni contrinsulari come in acromegalia e
sindrome Cushing.
• DM Gestazionale: intolleranza al glucosio che si
manifesta in ~4% delle gravidanze

8. Epidemiologia
• La prevalenza di DM di tipo II aumenta con lo
sviluppo industriale dei paesi essendo legato a
sedentarietà e obesità
• in USA il 7% della popolazione ha DM

9. Criteri di diagnosi di DM
Diagnosis and Classification
Table 2—Criteria for the diagnosis of diabetes Tab
1. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at
(A1
least 8 h.* reco
OR
2. Symptoms of hyperglycemia and a casual plasma glucose 200 mg/dl (11.1 Dia
mmol/l). Casual is defined as any time of day without regard to time since last The
meal. The classic symptoms of hyperglycemia include polyuria, polydipsia, and anc
unexplained weight loss. and
OR the
3. 2-h plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test Fo
should be performed as described by the World Health Organization, using a Con
glucose load containing the equivalent of 75 g anhydrous glucose dissolved in litu
water.* of t
teri
*In the absence of unequivocal hyperglycemia, these criteria should be confirmed by repeat testing on a
different day.
agn
are
Tes

10. Screening test per DM tipo II
• Uso della glicemia plasmatica a digiuno (FGP)
• Ogni 3 anni per soggetti >45 anni
• anche prima se BMI>25kg/m2 o altri fattori di
rischio

11. Fattori di rischio per DM II
2278 TABLE 338-3 RISK FACTORS FOR TYPE 2 DIABETES MELLITUS
Family history of diabetes (i.e., parent or sibling with type 2 diabetes) K+
Obesity (BMI ≥25 kg/m2) ATP-sensitive
Habitual physical inactivity K+ channel
Race/ethnicity (e.g., African American, Latino, Native American, Asian
American, Pacific Islander)
Previously identified IFG or IGT
History of GDM or delivery of baby >4 kg (>9 lb) ATP
Hypertension (blood pressure ≥140/90 mmHg)
HDL cholesterol level <35 mg/dL (0.90 mmol/L) and/or a triglyceride level Mitochondria
>250 mg/dL (2.82 mmol/L)
Polycystic ovary syndrome or acanthosis nigricans Pyruv
History of vascular disease
Note: BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose toler-
Glucose-6-p
ance; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein. G
Source: Adapted from American Diabetes Association, 2007. Glucos
GLUT2
(Table 338-3). In contrast to type 2 DM, a long asymptomatic period

12. Biosintesi dell’insulina
• In cellule β delle isole pancreatiche
• da precursore Preproinsulina (86AA)
• Insulina: catene A e B legate da ponte disolfuro
• Catena C secreta insieme a insulina. Ha un’emivita
plasmatica maggiore rispetto a insulina, utile a
discriminare se insulina è esogena o endogena in
ipoglicemia

13. Secrezione dell’insulina
• glucosio plasmatico è il regolatore principale della
secrezione di insulina
• livelli di glucosio plasmatico > 70mg/dL stimolano la
sintesi di insulina
• incretine (Glucagon-like peptide 1) stimolano secrezione
insulina dopo i pasti e riducono quella di glucagone.
Prodotte da cellule L intestino tenue. Analoghi come exan-tide
usati farmacologicamente.
• influenzata anche da AA, chetoni, altri nutrienti, peptidi GI

14. story of vascular disease transcription
Glucose-6-phosphate factors
ote: BMI, body mass index; IFG, impaired fasting glucose; IGT, impaired glucose toler-
Glucokinase
Glucosio e secrezione dell’insulina
ce; GDM, gestational diabetes mellitus; HDL, high-density lipoprotein.
urce: Adapted from American Diabetes Association, 2007. Glucose
Nucleus Insulin
GLUT2 Secretory
granules
ble 338-3). In contrast to type 2 DM, a long asymptomatic period
hyperglycemia is rare prior to the diagnosis of type 1 DM. A num- Glucose
of immunologic markers for type 1 DM are becoming available
Voltage dependent
cussed below), but their routine Ca2+ is discouraged2+pending the
+
use channel Ca
K FIGURE 338-4 Diabetes and abnormalities in glucose-stimulated
ntification of clinically beneficial interventions for individuals at
ATP-sensitive
h risk for+developing type 1 DM.Depolarization
K channel SUR insulin secretion. Glucose and other nutrients regulate insulin secre-
Incretins
tion by the pancreatic beta cell. Glucose is transported by the GLUT2
– Ca2+ glucose transporter; subsequent glucose metabolism by the beta cell
+
ULIN BIOSYNTHESIS, SECRETION, AND ACTION cAMP
ATP/ADP alters ion channel activity, leading to insulin secretion. The SUR recep-
SYNTHESIS Mitochondria tor is the binding site for drugs that act as insulin secretagogues. Mu-
vel
ulin is produced in the beta cells of the pancreatic islets. It is initial- tations in the events or proteins underlined are a cause of maturity
Islet
ynthesized as a single-chain 86-amino-acid precursor +
Pyruvate polypeptide, onset diabetes of the young (MODY) or other forms of diabetes. SUR,
transcription
proinsulin. Subsequent proteolytic processing removes the amino-
factors sulfonylurea receptor; ATP, adenosine triphosphate; ADP, adenosine
Glucose-6-phosphate
minal signal peptide, giving rise to proinsulin. Proinsulin is struc-
oler- diphosphate, cAMP, cyclic adenosine monophosphate. (Adapted from
Glucokinase
ally related to insulin-like growth factors I and II, which bind
Glucose WL Lowe, in JL Jameson (ed): Principles of Molecular Medicine. Totowa, NJ,
kly to the insulin receptor. Cleavage of an internal 31-residue Insulin
Nucleus frag- Humana, 1998.)
GLUT2
nt from proinsulin generates the C peptideSecretory A (21 amino ac-
and the
granules
eriod B (30 amino acids) chains of insulin, which are connected by
and ry bursts occurring about every 10 min, superimposed upon greater
num- Glucose
ulfide bonds. The mature insulin molecule and C peptide are stored amplitude oscillations of about 80–150 min. Incretins are released from
ilable
ether and cosecreted from secretory granules in the beta cells. Be- neuroendocrine cells of the gastrointestinal tract following food inges-
g the
als the C peptide is Diabetesmoreabnormalitiesinsulin, it is a useful
se at FIGURE 338-4 cleared and slowly than in glucose-stimulated tion and amplify glucose-stimulated insulin secretion and suppress glu-
rker of insulin secretion. Glucose and other nutrients regulate insulin secre-
insulin secretion and allows discrimination of endogenous cagon secretion. Glucagon-like peptide 1 (GLP-1), the most potent
exogenousby the pancreatic beta in the evaluation of hypoglycemia
tion sources of insulin cell. Glucose is transported by the GLUT2 incretin, is released from L cells in the small intestine and stimulates insu-
haps. 339 and transporter; subsequent glucose cosecrete isletthe beta cell
glucose 344). Pancreatic beta cells metabolism by amyloid lin secretion only when the blood glucose is above the fasting level. Incre-
ypeptide (IAPP) or amylin, a leading to insulin secretion. The SUR with
alters ion channel activity, 37-amino-acid peptide, along recep- tin analogues, such as exena-tide, are being used to enhance endogenous
tor is the binding site for drugs that act as insulin secretagogues. Mu-

15. Azione dell’insulina
• ~50% subito degradata dal fegato
• agisce su recettore tirosin chinasico
• Fosforilazione IRS e attivazione degli effetti metabolici
e mitogeni dell’insulina. Attiva sintesi proteica,
glicogeno sintesi, lipogenesi. Di solito resistenza solo
per effetti metabolici.
• principale controllore omesostasi glicemia
aumentando uptake e consumo periferico del glucosio

16. Glucagone
• glucagone secreto da cellule α isole pancreatiche
• secreto quando ci sono bassi livelli plasmatici di
insulina o glucosio
• stimola la gluconeogenesi e la glicogenolisi nel
fegato e nella midollare del rene

17. Patogenesi: DM tipo I
• completa o quasi totale deficienza di insulina,
distruzione β-cells
• risultato di fattori genetici, ambientali e
immunologici
• principalmente questa distruzione è di origine
autoimmune
• in alcuni casi l’autoimmunità non è dimostrata e il
meccanismo è sconosciuto

18. iabetes Mellitus
sponse by altering the beta cell destruction and most, but not all, individuals II
autoimmune binding affinity of different antigens for class
Beta cell mass (% of m
ates
have evidence of islet-directed autoimmunity. Some individuals who
ost- molecules. have the clinical phenotype of type 1 DM lack immunologic markers
Patogenesi: DM tipo I
on, Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplo-
indicative of an autoimmune process involving the beta cells. These in-
50
ne, type. Refinements inare thought to develop insulin have shown that thenon-
dividuals genotyping of HLA loci deficiency by unknown, hap-
The lotypes DQA1*0301,mechanisms andand DQB1*0201 are most African
immune DQB1*0302, are ketosis prone; many are strongly
an associated with type or DM. These haplotypes are present in 40% type 1
American 1 Asian in heritage. The temporal development of of chil- No diabetes
DM is shown schematically as a function of beta cell mass in Fig. 338-6. Diabetes
bly Individuals with a genetic susceptibility have normal beta cell mass at
birth but begin to lose beta cells secondary to autoimmune destruc- 0
Immunologic 0
tion that occurs over months to years. This autoimmune process is (Birth)
trigger Time (years)
thought to be triggered by an infectious or environmental stimulus
and to be sustained by a beta cell–specificabnormalities majority,
Immunologic molecule. In the FIGURE 338-6 Temporal model for development of type 1 diabe-
immunologic markers appear after the triggering event but before dia- tes. Individuals with a genetic predisposition are exposed to an im-
betes becomes clinically overt. Beta cell mass then begins to decline, munologic trigger that initiates an autoimmune process, resulting in a
Genetic
and insulin secretion becomes progressively impaired, although nor- gradual decline in beta cell mass. The downward slope of the beta cell
nd Progressive impairment
mal predisposition is maintained. The rate of decline in beta cell
glucose tolerance mass varies among individuals and may not be continuous. This pro-
he 100
of insulin release
mass varies widely among individuals, with some patients progressing gressive impairment in insulin release results in diabetes when ~80%
om of the beta cell mass is destroyed. A “honeymoon” phase may be seen
Beta cell mass (% of max)
rapidly to clinical diabetes and others evolving more slowly. Features
Overt diabetes
als of diabetes do not become evident until a majority of beta cells are de- in the first 1 or 2 years after the onset of diabetes and is associated
ho stroyed (~80%). At this point, residual functional beta cells still exist with reduced insulin requirements. [Adapted from Medical Manage-
but are insufficient in number to maintain glucose tolerance. The ment of Type 1 Diabetes, 3d ed, JS Skyler (ed). American Diabetes Associa-
ers events that trigger the transition from glucose intolerance to frank dia- tion, Alexandria, VA, 1998.]
in-
50
on-
an
e1 No diabetes
-6. Diabetes
at
uc- 0
0
is (Birth) Time (years)
lus
ty, FIGURE 338-6 Temporal model for development of type 1 diabe-
ia- tes. Individuals with a genetic predisposition are exposed to an im-

19. Patogenesi: DM tipo I
• la predisposizione al DM tipo I è multigenica,
principalmente su regione HLA del cromosoma 6
• cellule α, δ e PP sono risparmiate
dall’autoimmunità
• la distruzione è mediata principalmente dai
linfociti T
• cellule β molto sensibili a effetto tossico IL-1,TNF-
α, INF-γ

20. Patogenesi: DM tipo I
• Oltre ad Ab contro insulina, sono presenti anche
altri enzimi e proteine (ICAs - islet cells autoIg)
• ICAs non sono specifici solo delle cellule β, non si
sa perché le altre cellule siano risparmiate dal
processo autoimmune

21. Patogenesi: DM tipo II
• Resistenza insulinica o anormale secrezione
d’insulina: si pensa che la resistenza preceda la
l’inadeguata secrezione
• alta componente genetica: se entrambi i genitori
hanno DM di tipo II il rischio si avvicina al 40%
• malattia poligenica e multifattoriale influenzata
da obesità, alimentazione e attività fisica

22. Patogenesi: DM tipo II
• caratteristiche DM tipo 2:
• ridotta secrezione di insulina
• resistenza all’insulina
• eccessiva produzione di glucosio a livello epatico
per resistenza insulinica
• alterato metabolismo lipidico (↑LDL, ↑TGL, ↓HDL)
• obesità centrale

23. Patogenesi: DM tipo II
secrezione ⇔ resistenza
A-B) resistenza insulinica oxyge
transd
compensata da aumentata contro
1000 protei
secrezione (iperinsulinemia) the in
Insulin secretion
(pmol per min)
betes-
Th
• IGT, iperglicemia postprandiale B
viscer
increa
NGT fatty a
• iperglicemia a digiuno 500
D
C
IGT A
cytes
acids,
tin). I
Type 2 DM
• le cellule β vanno incontro a 0
0 50 100
pendi
produ
resista
esaurimento Insulin sensitivity
M value (µmol/min per kg) pair g
tion b
FIGURE 338-7 Metabolic changes during the development of produ
type 2 diabetes mellitus (DM). Insulin secretion and insulin sensitiv- tide, i
ity are related, and as an individual becomes more insulin resistant (by resista
moving from point A to point B), insulin secretion increases. A failure flamm

24. Anomalie metaboliche: DM tipo II
• resistenza dovuta a minor numero recettori e a
difetti nella trasduzione del segnale
• si accumulano lipidi in fibrocellule muscolari con
formazione di perossidi
• l’effetto mitogeno dell’insulina non è soggetto a
resistenza con ↑ rischio aterosclerotico

25. Anomalie metaboliche: DM tipo II
• ↑ t. adiposo ⇒↑ di acidi grassi liberi in plasma e ↑
prodotto adipociti (retinol binding protein 4, leptina,
TNF-α ecc..)
• Adipochine regolano a loro volta la resistenza
insulinica alcune producono uno stato
infiammatorio che spiega marker infiammatori
spesso alti in DM 2 (↑IL-6, ↑PCR)
• acidi grassi diminuiscono utilizzo glucosio nei
muscoli e aumentano produzione di glucosio epatica

26. Prevenzione DM tipo II
• DM tipo 2 è preceduto da un periodo di
intolleranza al glucosio (IGT)
• cambiamenti dello stile di vita e farmaci ne
ritardano la comparsa
• dieta
• esercizio fisico 30min/die, 5 gg a settimana
• in casi particolari, seguendo le linee guida, la
metformina può essere somministrata.

27. Compicazioni acute del DM
• Acute
• Chetoacidosi
• Stato iperglicemico iperosmolare

28. Acute: chetoacidosi diabetica
• deficit di insulina relativo o assoluto con aumento
degli ormoni contrinsulari (glucacone,
catecolammine, cortisolo, GH)
• necessari sia deficit insulina che eccesso glucagone
• aumento del rilascio di acidi grassi da adipociti e
formazione di corpi chetonici nel fegato
• chetoni neutralizzati da bicarbonato
• sviluppo di acidosi metabolica

29. In chetoacidosi
β-idrossibutirrato:acetoacetato=3:1

30. TABLE 338-5 MANIFESTATIONS OF DIABETIC KETOACIDOSIS wh
ol
Symptoms Physical findings bi
Nausea/vomiting Tachycardia
Thirst/polyuria Dehydration/hypotension
su
Abdominal pain Tachypnea/Kussmaul respirations/ Th
Shortness of breath respiratory distress VL
Precipitating events Abdominal tenderness (may tiv
Inadequate insulin administration resemble acute pancreatitis or de
Infection (pneumonia/UTI/ surgical abdomen)
gastroenteritis/sepsis) Lethargy/obtundation/cerebral
Infarction (cerebral, coronary, edema/possibly coma
M
mesenteric, peripheral) m
Alito acetonemico
Drugs (cocaine) (odore frutta marcia) in
Pregnancy om
Note: UTI, urinary tract infection.
ize
in
sin

31. Laboratoio: chetoacidosi diabetica
• iperglicemia
• chetosi
• acidosi metabolica (↑ gap anionico), spesso
Bicarbonato <10mmol/L, pH 6.8-7.3
• kaliemia leggermente elevata per acidosi
• ↓ Total body K, Na, Mg e Fosfati per
disidratazione

32. Management di chetoacidosi diabetica
• reidratazione
• terapia con insulina short-acting
• curo l’evento che ha fatto precipitare la situazione
• valuto glicemia e parametri vitali
• a seconda dei dati di lab somministro potassio

33. Stato iperglicemico iperosmolare
• di solito soggetto anziano con DM tipo II
• con storia di poliuria, perdita peso ridotta
idratazione
• Si presenta con iperosmolarità iponatriemica,
ipotensione, tachicardia, status mentale alterato

34. Stato iperglicemico iperosmolare
• Sono assenti sintomi di nausea, vomito, dolore
addominale e il segno del respiro di Kussmaul
• L’evento precipitante può essere un infarto o un
ictus ma anche polmonite, sepsi e altre infezioni

35. Stato iperglicemico iperosmolare
• causato da deficit relativo di insulina e ridotta
assunzione di H2O
• iperglicemia responsabile della diuresi osmotica
• dati di laboratorio:
• iperglicemia, può essere >1000mg/dL
• iperosmolarità, >350mosm/L
• azotemia prerenale

36. Stato iperglicemico iperosmolare
• Management simile a quello per la chetoacidosi

37. Complicazioni croniche del DM
• coinvolgono molti organi
• associate ad alta morbidità e mortalità
• il rischio di microangiopatia (oftalmoparie, neurpopatie,
nefropatie) aumenta in funzione della durata
dell’iperglicemia
• anche la malattia coronarica correla con iperglicemia
• dislipidemia e ipertensione giocano un ruolo importante
nelle macroangiopatie
• fattori genetici ne influenzano la comparsa

38. the development of macrovascular complications is less conclusive.
s of both HHS
eral elements
patient’s fluid TABLE 338-7 CHRONIC COMPLICATIONS OF DIABETES MELLITUS
Underlying or Microvascular
eated. In HHS, Eye disease
than in DKA Retinopathy (nonproliferative/proliferative)
HHS is usually Macular edema
kely to have a Neuropathy
comorbidities. Sensory and motor (mono- and polyneuropathy)
mortality than Autonomic
Nephropathy
Macrovascular
amic status of Coronary artery disease
. Because the Peripheral arterial disease
weeks, the ra- Cerebrovascular disease
need for free Other
worsen neuro- Gastrointestinal (gastroparesis, diarrhea)
/L), 0.45% sa- Genitourinary (uropathy/sexual dysfunction)
d, the IV fluid Dermatologic
sing hypoton- Infectious
W). The calcu- Cataracts
Glaucoma
reversed over Periodontal disease
onic solution).

39. Meccanismi
esistono 4 ipotesi per spiegare la correlazione fra iperglicemia e
complicazioni croniche (non sono mutualmente escusive)
1. glicosilazione non enzimatica di proteine. Si ha un’aumentata
aterosclerosi, disfunzione endoteliale e di NOS, alterazione della
matrice extracellulare e riduzione della funzione glomerualare
2. produzione di sorbitolo che genera ROS
3. attivazione PKC con attivazione espressione geni per
fibronectina, collagene IV tipo, matrice extracellulare in neuroni e
cellule endoteliali
4. alterazione NOS, e aumentata espressione TGF-β

40. Meccanismi
• Grow factors sembrano giocare un ruolo importante in
tutti questi meccanismi proposti
• L’iperglicemia è comunque il fattore scatenante per le
complicazioni diabetiche
• il gruppo di pz. con uno stretto controllo della glicemia
sviluppa meno complicazioni rispetto a quello con
terapia standard
• A1C mantenuta al 7% e il controllo della pressione
arteriosa prevengono molte complicazioni

41. Tra le ipotesi patogenetiche delle complicanze del diabete un ruolo
fondamentale ricoprono gli effetti di elevate concentrazioni di glucosio
e conseguente formazione di Prodotti tardivi della glicosilazione non
enzimatica (Advanced Glycation Endproducts o AGE) a livello delle
proteine circolanti e strutturali. Il legame degli AGE a tali
macromolecole ne determina dapprima alterazioni funzionali e in fasi
successive anche modificazioni a livello dei tessuti di appartenenza. I
fenomeni riscontrati in corso di diabete mellito sono sovrapponibili
a quelli che si verificano nell'invecchiamento tanto che quest'ultimo
fenomeno appare determinato dall'esposizione dei tessuti a normali
concentrazioni di glucosio per un periodo di tempo prolungato. Un
intervento terapeutico atto ad ridurre la formazione degli AGE a livello
tessutale potrebbe prevenire sia il danno strutturale indotto dal diabete
mellito sia le modificazioni tipiche dell’invecchiamento.

42. Complicazioni oftamologiche del DM
• causa principale di cecità nell’adulto negli usa
• cecità dovuta a retinopatia diabetica ed edema
maculare

43. Retinopatia
• classificata in 2 stages:
• non proliferativa (nei primi 10-15 anni)
• microaneurismi della vascolatura retinica
• microemorragie
• «macchie di cotone»
• aumento calibro vasi venosi
• perdita periciti retinici, aumento permeabilità e
alterazioni del flusso portano a ischemia della retina
(angiografia con fluorescina)

44. of intensive glycemic control and risk factor treatment on the develop- 228
ment of diabetic complications. Newly diagnosed individuals with
type 2 DM were randomized to (1) intensive management using vari-
ous combinations of insulin, a sulfonylurea, or metformin; or (2) con-
ventional therapy using dietary modification and pharmacotherapy
with the goal of symptom prevention. In addition, individuals were
randomly assigned to different antihypertensive regimens. Individuals
in the intensive treatment arm achieved an A1C of 7.0%, compared to
a 7.9% A1C in the standard treatment group. The UKPDS demon-
strated that each percentage point reduction in A1C was associated
with a 35% reduction in microvascular complications. As in the
DCCT, there was a continuous relationship between glycemic control
and development of complications. Improved glycemic control did
not conclusively reduce (nor worsen) cardiovascular mortality but was
associated with improvement with lipoprotein risk profiles, such as re-
duced triglycerides and increased HDL. FIGURE 338-9 Diabetic retinopathy results in scattered hemor-
One of the major findings of the UKPDS was that strict blood pres- rhages, yellow exudates, and neovascularization. This patient
sure control significantly reduced both macro- and microvascular has neovascular vessels proliferating from the optic disc, requiring ur-
complications. In fact, the beneficial effects of blood pressure control gent pan retinal laser photocoagulation.
were greater than the beneficial effects of glycemic control. Lowering
blood pressure to moderate goals (144/82 mmHg) reduced the risk of
CHAPTER
DM-related death, stroke, microvascular end points, retinopathy, and Duration of DM and degree of glycemic control are the best predic-
heart failure (risk reductions between 32 and 56%). tors of the development of retinopathy; hypertension is also a risk fac-
Similar reductions in the risks of retinopathy and nephropathy were tor. Nonproliferative retinopathy is found in almost all individuals

45. Retinopatia
• proliferativa, neovascolarizzazione in risposta a ipossia
• i vasi neoformati (vicino a nervo ottico e/o macula) sono
molto delicati
• si rompono facilmente portando a emorragia in corpo vitreo,
fibrosi che evolvono in distacco della retina per retrazione
della ciccatrice
• la pressione alta è un fattore di rischio e precipitante di
retinopatia
• trammento con controllo glicemia, pressione, fotocoagulazione,
limitare esercizi con manovre di Valsava ripetute

46. Nefropatia diabetica
• causa principale di end stage renal disease in USA
• microalbinuria e macroalbinuria in pz. con DM
associate a maggior rischio di malattia cardiovascolare
• microalbuminuria più comune in DM 2 per esordio
lento malattia oppure perché conseguenza di
ipertensione
• controllo glicemia, pressione, trattamento con ACE
inibitori o bloccanti per recettore AgII (ARBs), controllo
dislipidemia

47. Una delle manifestazioni precoci della nefropatia diabetica è
rappresentata dall' alterazione della permselettività a livello della
membrana basale glomerulare. In condizioni normali, cariche
elettrostatiche negative costituite da eparansolfato ed acido
sialico, presenti a livello glomerulare si oppongono all' aumento
della filtrazione delle proteine circolanti. Nelle fasi precoci della
nefropatia è stata dimostrata una diminuzione di tali cariche
negative per cui maggiori quantità di proteine elettronegative
(proteinuria selettiva per carica) viene eliminata con le urine. Il
rilievo di tale proteinuria in pazienti diabetici può rappresentare
un segno precoce di nefropatia. In base a tale riscontro è possibile
iniziare, in pazienti selezionati, interventi terapeutici atti a
ritardare la progressione di tale complicanza.

48. Storia naturale della nefropatia diabetica
Anni dopo
Fase Alterazione GFR
diagnosi
A. Ipertrofia funzionale alterazioni emodinamiche ↑ 1
B. Incipiente iniziale perdita selettività di carica
5-10
C. Incipiente terminale microalbuminoria (30-300mg/die) normale
perdita selettività di volume
D. Conclamata o clinica ↓ 15-20
macroalbuminuria (3g/die)
perdita selettività di volume
E. Insufficienza renale ↓↓ 22-30
riduzione proteinuria (200mg/24h)
coma uremico o iperazotemico
F. Nefrosi e uremia chiusura glocerulare 0
riduzione proteinuria

50. Neuropatia diabetica
• Complicazione di ~50% DM (lunga durata)
• polineuropatia
• mononeuropatia
• autonomopatia
• rischio aumentato da fumo e BMI alto
• diagnosi per esclusione di altre neuropatie
• importante lo screening periodico dei pz. con DM

51. Polineuropatia/mononeuropatia
• più comune forma è la polineuropatia distale
simmetrica. Vi è perdita sensibilità
• tuttavia anche iperestesia, parestesia o disestesia
possono presentarsi da sole o combinate
• è comune il dolore a riposo agli arti inferiori che
con l’avanzare della neuropatia scompare
lasciando spazio all’insensibilità
•

52. Polineuropatia/mononeuropatia
• poliradiculopatia: dolore disabilitante che
coinvolge una o più radici posteriori, può essere
accompagnata da debolezza muscolare,
autolimitanti
• mononeuropatia la più comune coinvolge III n.
cranico (oculomotore), si manifesta con diplopia.
A volte coinvolge altri n. cranici IV, VI, VII
(paralisi di Bell)

53. Autonomopatia
• coinvolge sistemi colinergici, adrenergici e
peptidergici (peptide pancreatico, sostanza P)
• cardiovascolare - tachicardia a riposo (vagolisi)
ipotensione ortostatica - morte improvvisa.
• genitourinario - ileo paralitico e difetti minzione
• sudomotore - iperidrosi estremita superiori e
anidrosi delle inferiori (favorisce rottura cute e
ulcera, piede diabetico)

54. Autonomopatia
• difetti nel sentire l’ipoglicemia

55. Complicazioni agli arti inferiori
• prima causa di aumputazione non ascrivibile a
trauma
• ulcere e infezioni sono la prima fonte di morbidità
in pz. con DM
• neuropatia con conseguente alterata biomeccanica
del piede
• arteriopatia periferica
• scarsa guarigione delle ferite

56. Complicazioni agli arti inferiori
• problemi nella propiocezioni alterano da
distribuzione del peso sul piede
• aumentata soglia del dolore rende microtraumi
non coscienti
• anidrosi e fissurazione cute
• ampi calli spesso precedono ulcera

57. Infezioni in DM
• aumentata frequenza e gravità delle infezioni
• ↓immunità cellulo-mediata e fagocitosi con
iperglicemia
• ridotta vascolarizzazione
• iperglicemia favorisce crescita microrganismi
• otite esterna da P. Aeruginosa
• polmoniti, UTIs, celluliti

58. Rischio cardiovascolare
• in DM maggior prevalenza di malattie
cardiovascolari
• spesso c’è assenza di dolore ischemico in DM per
neuropatia
•

59. Manifestazioni dermatologiche
• allungamento tempo guarigione ferite e ulcere
• papule pretibiali pigmentate (in seguito a piccoli
traumi)

60. Esame fisico
• BMI
• esame del fundus
• pressione ortostatica
• ispezione dei piedi
• polsi periferici
• ispezione aree di iniezione di insulina
• sensibilità periferica

61. TABLE 338-8 TREATMENT GOALS FOR ADULTS WITH DIABETES a Nutrition Medic
Index Goal to describe the op
of diabetes therap
Glycemic controlb recommendations
A1C <7.0c sures of MNT are
Preprandial capillary plasma 5.0–7.2 mmol/L (90–130 mg/dL) DM in high-risk i
glucose
Peak postprandial capillary plasma <10.0 mmol/L (<180 mg/dL)d weight reduction.
glucose and is discussed i
Blood pressure <130/80e are directed at pre
Lipidsf diabetic individua
Low-density lipoprotein <2.6 mmol/L (<100 mg/dL) measures of MNT
High-density lipoprotein >1.1 mmol/L (>40 mg/dL)g tions (cardiovascu
Triglycerides <1.7 mmol/L (<150 mg/dL)
example, in indiv
aAs recommended by the ADA; Goals should be developed for each patient (see text). tein intake should
Goals may be different for certain patient populations. patients with diab
bA1C is primary goal.
cWhile the ADA recommends an A1C < 7.0% in general, in the individual patient it rec-
etary principles u
ommends an “. . . A1C as close to normal (<6.0%) as possible without significant hy-
ease. While the re
poglycemia. . . .” Normal range for A1C—4.0–6.0 (DCCT-based assay). this chapter emph
dOne-two hours after beginning of a meal. macologic approa
eIn patients with reduced GFR and macroalbuminuria, the goal is <125/75. should be conside
fIn decreasing order of priority.
As for the gene
gFor women, some suggest a goal that is 0.25 mmol/L (10 mg/dL) higher.
fiber-containing f
Source: Adapted from American Diabetes Association, 2007.
of DM therapy, M

62. TABLE 338-9 NUTRITIONAL RECOMMENDATIONS FOR ADULTS Exercise Exercise
WITH DIABETES a cular risk reductio
mass, reduction in
Fat 1 or type 2 DM,
20–35% of total caloric intake
(during and follow
Saturated fat < 7% of total calories
<200 mg/day of dietary cholesterol patients with diabe
Two or more servings of fish/week provide -3 polyunsaturated fatty ed over at least 3 d
acids 2 DM, the exercise
Minimal trans fat consumption Despite its bene
Carbohydrate DM because they
45–65% of total caloric intake (low-carbohydrate diets are not
mally, insulin falls
recommended)
Amount and type of carbohydrate importantb is a major site for m
Sucrose-containing foods may be consumed with adjustments in insulin the increased musc
dose increases fuel requ
Protein either hyperglycem
10–35% of total caloric intake (high-protein diets are not recommended) the preexercise pla
Other components
level of exercise-in
Fiber-containing foods may reduce postprandial glucose excursions
Nonnutrient sweeteners the rise in catechol
promote ketone b
aSeetext for differences for patients with type 1 or type 2 diabetes. As for the general Conversely, if the c
population, a healthy diet includes fruits, vegetables, and fiber-containing foods.
bAmount of carbohydrate determined by estimating grams of carbohydrate in diet; gly-
perinsulinemia m
cemic index reflects how consumption of a particular food affects the blood glucose. glycogenolysis, dec
Source: Adapted from American Diabetes Association, 2007. into muscle, leadin
To avoid exercis

63. 98 Morning Afternoon Evening Night
Insulin Insulin Insulin Morning Afternoon Evening Night Morning Afternoon Evening Night
ana- ana- ana- Insulin Insulin
Insulin effect
Insulin effect
Insulin effect
logue* logue* logue* analogue* analogue* Bolus Bolus Bolus
Regular Regular
Basal Infusion
NPH^
Glargine^ NPH^
B L S HS B B L S HS B B L S HS B
Meals Meals Meals
A B C
FIGURE 338-13 Representative insulin regimens for the treat- meal. B. The injection of two shots of long-acting insulin (^, NPH or
ment of diabetes. For each panel, the y-axis shows the amount of in- detemir) and short-acting insulin [glulisine, lispro, insulin aspart (solid
sulin effect and the x-axis shows the time of day. B, breakfast; L, lunch; red line), or regular (green dashed line)]. Only one formulation of
S, supper; HS, bedtime; CSII, continuous subcutaneous insulin infusion. short-acting insulin is used. C. Insulin administration by insulin infu-
*Lispro, glulisine, or insulin aspart can be used. The time of insulin in- sion device is shown with the basal insulin and a bolus injection at
jection is shown with a vertical arrow. The type of insulin is noted each meal. The basal insulin rate is decreased during the evening and
above each insulin curve. A. A multiple-component insulin regimen increased slightly prior to the patient awakening in the morning.
consisting of long-acting insulin (^, one shot of glargine or two shots Glulisine, lispro, or insulin aspart is used in the insulin pump. [Adapted
of detemir) to provide basal insulin coverage and three shots of from H Lebovitz (ed): Therapy for Diabetes Mellitus. American Diabetes As-
glulisine, lispro, or insulin aspart to provide glycemic coverage for each sociation, Alexandria, VA, 2004.]
ma glucose measurements. In general, individuals with type 1 DM require mal regimen for the patient with type 1 DM, but is sometimes used for
0.5–1.0 U/kg per day of insulin divided into multiple doses, with ~50% of patients with type 2 diabetes.
the insulin given as basal insulin. Continuous subcutaneous insulin infusion (CSII) is a very effective insulin
Multiple-component insulin regimens refer to the combination of basal regimen for the patient with type 1 diabetes (Fig. 338-13C). To the basal in-

64. Diabetes Mellitus
TABLE 383-11 GLUCOSE-LOWERING THERAPIES FOR TYPE 2 DIABETES
A1C Contraindications/
Mechanism Reduction Agent-Specific Agent-Specific Relative
of Action Examples (%)a Advantages Disadvantages Contraindications
Oral
Biguanides Hepatic glucose Metformin 1–2 Weight loss Lactic acidosis, diarrhea, Serum creatinine >1.5
production, nausea mg/dL (men) >1.4
weight loss, glu- mg/dL (women), CHF,
cose, utilization, radiographic contrast
insulin resistance studies, seriously ill
patients, acidosis
–Glucosidase Glucose Acarbose, 0.5–0.8 Reduce postpran- GI flatulence, liver Renal/liver disease
inhibitors absorption Miglitol dial glycemia function tests
Dipeptidyl Prolong endoge- Sitagliptin 0.5–1.0 Does not cause Reduce dose with renal
peptidase IV nous GLP-1 action hypoglycemia disease
inhibitors
Insulin secreta- Insulin secretion Table 338-12 1–2 Lower fasting Hypoglycemia, weight Renal/liver disease
gogues— blood glucose gain
sulfonylureas
Insulin secreta- Insulin secretion Table 338-12 1–2 Short onset of ac- Hypoglycemia Renal/liver disease
gogues—non- tion, lowers post-
sulfonylureas prandial glucose
Thiazolidinedi- Insulin resistance, Rosiglitazone, 0.5–1.4 Lower insulin Peripheral edema, CHF, Congestive heart fail-
ones glucose Pioglitazone requirements weight gain, fractures, ure, liver disease
utilization macular edema;
rosiglitazone may
increase risk of MI
Parenteral
Insulin Glucose utiliza- Table 323-11 No limit Known safety Injection, weight gain,
tion and other profile hypoglycemia
anabolic actions
GLP-1 agonist Insulin, Gluca- Exenatide 0.5–1.0 Weight loss Injection, nausea, risk Renal disease, agents
gon, slow gastric of hypoglycemia with that also slow GI
emptying insulin secretagogues motility
Amylin agonistb Slow gastric empty- Pramlintide 0.25–0.5 Reduce postpran- Injection, nausea, risk Agents that also slow
ing, Glucagon dial glycemia, of hypoglycemia with GI motility
weight loss insulin
Medical nutrition Insulin, resistance, Low-calorie, 1–2 Other health Compliance difficult,
therapy and insulin secretion low-fat diet, benefits long-term success low
physical activity exercise
aA1C reduction depends partly on starting A1C.
bAmylin agonist is approved for use in type 1 and type 2 diabetes.

65. TABLE 339-1 CAUSES OF HYPOGLYCEMIA 23
339
Ipoglicemia
Hypoglycemia
Philip E. Cryer
Fasting (Postabsorptive) Hypoglycemia
Drugs
Especially insulin, sulfonylureas, ethanol
Hypoglycemia is most commonly caused by drugs used to treat diabe- Sometimes quinine, pentamidine
Rarely salicylates, sulfonamides, others
tes mellitus or by exposure to other drugs, including alcohol. However, Critical illnesses
a number of other disorders, including insulinoma, critical organ fail- Hepatic, renal, or cardiac failure
ure, sepsis and inanition, hormone deficiencies, non-β-cell tumors, in-
• la causa più comune più
herited metabolic disorders, and prior gastric surgery, may cause
Sepsis
Inanition
iatrogena
hypoglycemia (Table 339-1). Hypoglycemia is most convincingly docu- Hormone deficiencies
Cortisol, growth hormone, or both
mented by Whipple’s triad: (1) symptoms consistent with hypoglyce-
Glucagon and epinephrine (in insulin-deficient diabetes)
mia, (2) a low plasma glucose concentration measured with a precise
• con neuropatia autonomica
method (not a glucose monitor), and (3) relief of those symptoms after
Non-β-cell tumors
Endogenous hyperinsulinism
the plasma glucose level is raised. The lower limit of the fasting plasma
minor sensibilità a sintomi
glucose concentration is normally approximately 70 mg/dL (3.9 mmol/L),
Insulinoma
Other β cell disorders
Insulin secretagogue (sulfonylurea, other)
ipoglicemia
but substantially lower venous glucose levels occur normally, late after a
Autoimmune (autoantibodies to insulin or the insulin receptor)
meal. Glucose levels <55 mg/dL (3.0 mmol/L) with symptoms that are
Ectopic insulin secretion
relieved promptly after the glucose level is raised document hypoglyce-
mia. • triade di Whipplemorbidity; if severe and pro-
Disorders of infancy or childhood
Hypoglycemia can cause serious Transient intolerance of fasting
longed, it can be fatal. It should be considered in any patient with Congenital hyperinsulinism
episodes• confusion, an altered level of consciousness, or a seizure.
of sintomi Inherited enzyme deficiencies
Reactive (Postprandial) Hypoglycemia
SYSTEMIC GLUCOSE BALANCE AND
•COUNTERREGULATION
basso glucosio plasmatico Alimentary (postgastrectomy)
GLUCOSE Noninsulinoma pancreatogenous hypoglycemia syndrome
Glucose is an obligate metabolic fuel for the brain under physiologic In the absence of prior surgery
• scomparsa dei sintomi con
conditions. The brain cannot synthesize glucose or store more than a Following Roux-en-Y-gastric bypass
Other causes of endogenous hyperinsulinism
few minutes’somministrazione di glucosio
supply as glycogen and therefore requires a continuous Hereditary fructose intolerance, galactosemia
supply of glucose from the arterial circulation. As the arterial plasma Idiopathic
glucose concentration falls below the physiologic range, blood-to-

66. Sintomi e segni ipoglicemia
• confusione mentale
• faticabilità
• perdità di conoscenza
• si può arrivare a morte

67. Sintomi e segni ipoglicemia
• sintomi mediati da sistema simpatico (e da adrenalina rilasciata
dalla midollare del surrene)
• palpitazione, tremore e agitazione
• sintomi mediato da sistema parasimpatico
• sudure, fame e parestesia
• diaforesi e pallore
• aumento freq. cardiaca e pressione

68. e. Between meals
sma glucose lev- Arterial Glucose
endogenous glu- Liver
c glycogenolysis, Pancreas
gluconeogenesis Insulin
hepatic glycogen
Brain
ient to maintain Glucagon Kidneys Glucose
or approximately production
can be shorter if
eased by exercise
e depleted by ill- Sympathoadrenal
outflow Arterial
Pituitary glucose
quires a coordi- Muscle Fat
ors from muscle
Adrenal
he liver (and kid-
medullae
lactate, pyruvate, Gluconeogenic
other amino ac- Growth Epinephrine precursor (lactate,
dipose tissue are hormone amino acids, glycerol)
acids and glycer- (ACTH) Sympathetic
postganglionic Glucose
ogenic precursor. clearance
neurons
lternative oxida- Adrenal (Ingestion)
Norepinephrine
r than the brain cortex
Symptoms
).
Acetylcholine
alance—mainte-
Cortisol
plasma glucose
omplished by a FIGURE 339-1 Physiology of glucose counterregulation—the mechanisms that normally pre-
, neural signals, vent or rapidly correct hypoglycemia. In insulin-deficient diabetes, the key counterregulatory re-
hat regulate en- sponses—suppression of insulin and increases of glucagon—are lost, and the stimulation of
duction and glu- sympathoadrenal outflow is attenuated.

69. 2306 TABLE 339-2 PHYSIOLOGIC RESPONSES TO DECREASING PLASMA GLUCOSE CONCENTRATIONS C
diap
Glycemic Role in the Prevention or ic b
Threshold, Physiologic Correction of Hypoglycemia thes
Response mmol/L (mg/dL) Effects (Glucose Counterregulation)
rogl
↓ Insulin 4.4–4.7 (80–85) ↑ Ra (↓Rd) Primary glucose regulatory factor/first serv
defense against hypoglycemia occu
↑ Glucagon 3.6–3.9 (65–70) ↑ Ra Primary glucose counterregulatory defi
factor/second defense against
hypoglycemia ETIO
↑ Epinephrine 3.6–3.9 (65–70) ↑ Ra, ↓ Rc Third defense against hypoglycemia,
Hyp
critical when glucagon is deficient
↑ Cortisol and 3.6–3.9 (65–70) ↑ Ra, ↓ R c Involved in defense against pro- the
growth hormone longed hypoglycemia, not critical fore
Symptoms 2.8–3.1 (50–55) Recognition of Prompt behavioral defense against es o
hypoglycemia hypoglycemia (food ingestion)
↓ Cognition <2.8 (<50) — (Compromises behavioral defense HYP
against hypoglycemia) Imp
Note: Ra, rate of glucose appearance, glucose production by the liver and kidneys; Rc, rate of glucose clearance, glu- limi
cose utilization relative to the ambient plasma glucose concentration; Rd, rate of glucose disappearance, glucose utili- of d
zation by the brain (which is unaltered by the glucoregulatory hormones) and by insulin-sensitive tissues such as bidi
skeletal muscle (which is regulated by insulin, epinephrine, cortisol, and growth hormone). (T1
(T2

70. HYPOGLYCEMIA-ASSOCIATED AUTONOMIC FAILURE
Insulin deficient diabetes
(Imperfect insulin replacement)
(No ↓ insulin, no ↑ glucagon)
Antecedent hypoglycemia
• limite inferiore di glicemia
plasmatica a digiuno è Sleep
Reduced sympathoadrenal
responses to hypoglycemia
Antecedent
70mg/dL, ma nel plasma exercise
venoso può essere anche Reduced sympathetic Reduced epinephrine
neural responses responses
più bassa
Hypoglycemia Defective glucose
unawareness counterregulation
Recurrent hypoglycemia
FIGURE 339-2 Hypoglycemia-associated autonomic failure in in-
sulin-deficient diabetes. (Adapted from Cryer PE: N Engl J Med
350:2272, 2004. Copyright Massachusetts Medical Society, 2004.)

71. in
hypoglycemia excluded
and laboratory features with insulinoma. It 2309
ALGORITHM APPROACH TO PATIENT is most common among health care work- RE
ers, patients with diabetes or their relatives, H
Suspected/Documented Hypoglycemia FIGURE 339-3 Diagnostic approach to a patient with documented hypoglycemia or sus-
w
pected hypoglycemia based onandhistorywithsuggestive symptoms, a low plasma glucose concen-
a people of a history of other factitious
illnesses. However, it should be considered of
tration, or both. Ab+, positive in all antibody to evaluated for hypogly-
for patients being insulin; SU+, positive for sulfonylurea (or other
Diabetes No diabetes sc
secretagogue). cemia of obscure cause. Accidental inges- se
tion of an insulin secretagogue (e.g., the
result of a pharmacy error) also occurs. to
Treated with Clinical clues Apparentlyconceptually attractive treatment, although controlled clinical tri-
is a healthy Analytical error in the measurement of essary in patients with suspe
• Insulin • Drugs als documenting its efficacy are lacking.
• Sulfonylurea • Organ failure
plasma glucose concentrations is rare. On drawn, whenever possible, bef
• Other secretagogue • Sepsis Fasting Reactive hypoglycemia also occurs in hand, glucose monitors used to
glucose the other patients with autoantibodies low documentation of a low p
• Hormone deficiencies to insulin and in the noninsulinomatreatment of diabetes are not quanti-
guide pancreatogenous hypoglycemia ing documentation of hypo
• Non-β-cell tumor
Adjust regimen • Previous gastric
syndrome. Affected patients have instruments, particularly at low glu-
tative symptomatic hyperinsulinemic
Whipple’s triad. Thus, the ide
cose levels, and these should not be used
<55 mg/dL ≥55 mg/dL hypoglycemia (but negative 72-h fasts) that remits fol-
surgery postprandial for the definitive diagnosis of hypoglyce- level is during a symptomati
lowing partial pancreatectomy. Histologic findings include β celllow
mia. Even with a quantitative method, hy- cludes hypoglycemia as the c
Document improve-
ment and monitor Provide adequate pertrophy with or without hyperplasia. A similar syndrome can be ar-
History measured glucose concentrations following level confirms that hypoglycem
glucose, treat Roux-en-Y gastric bypass surgery for obesitythe result of continued glu-
tifactual, e.g., has been described. vided the latter resolve after
underlying cause Strong existence of a clinically relevant idiopathic reactive elements of
cose metabolism by the formed hypoglyce-
The Weak cause of the hypoglycemic ep
mia syndrome is debated. The issue is whether particularly in thecaused
the blood ex vivo,
symptoms are pres- ments, while the glucose level
CHAPTER 339 Hypoglycemia
ence of leukocytosis, erythrocytosis, or
by hypoglycemia, an exaggerated sympathoadrenal separation of the se-
Extended fast thrombocytosis, or if response to declin- clude plasma insulin, C-pepti
ing glucose levels late after a rum from the formed elements is delayed
meal, or some glucose-independent as levels of insulin secretagogu
mechanism. In any event, caution should be exercised before labeling a
Glucose (pseudohypoglycemia). When the history suggests
person with a diagnosis of hypoglycemia. Frequent feedings, avoid- mechanism is not apparent, th
ance of simple sugars, and high-protein diets are commonly recom- plasma glucose, insulin, and C
↑ Insulin, Whipple’s triad <55 mg/dL ≥55 mg/dL APPROACH TO THE PATIENT:
mended to patients thought to have idiopathic reactive hypoglycemia.
Hypoglycemia hypoglycemia would be expe
The efficacy of these approaches has not been established by con- other hand, while it cannot b
↑ C-peptide ↓ C-peptide trolled clinical trials.
Mixed meal In addition to recognition and docu- cose concentration measured
mentation of hypoglycemia, and often
symptoms raises the possibilit
urgent treatment, diagnosis of the hy-
Ab+ SU+ FACTITIOUS AND ARTIFACTUAL HYPOGLYCEMIA mechanism is critical for
poglycemic
Exogenous Whipple’s No Whipple’s DIAGNOSIS OF THE HYPOGLYCEM
Factitious hypoglycemia, caused by surreptitious or even prevents, or ad-
choosing a treatment that malicious
Insulinoma Autoimmune Sulfonylurea insulin triad triad documented hypoglycemia, a
ministration of insulin or an insulinleast minimizes, shares many clinical
at secretagogue, recurrent hypogly-
cemia. A diagnostic algorithm is shown
Likely factitious Reactive Hypoglycemia in Fig. 339-3.
hypoglycemia excluded
RECOGNITION AND DOCUMENTATION
Hypoglycemia is suspected in patients