The metabolism of glucose

CARBOHYDRATECARBOHYDRATESS
METABOLISMMETABOLISM
DISORDERSDISORDERS

GLUCOSE METABOLISMGLUCOSE METABOLISM
 the cornerstone of lifethe cornerstone of life
 neurons are especially dependent onneurons are especially dependent on
glucoseglucose
 regulatory mechanisms:regulatory mechanisms:

hyperglycemic hormones = glycogenolysis,hyperglycemic hormones = glycogenolysis,
gluconeogenesisgluconeogenesis

hypoglycemic hormone = insulinhypoglycemic hormone = insulin

liv e r s to r a g e
g ly c o g e n
g lu c o s e m o v e s in to
in s u lin -d e p e n d e n t c e lls
(m u s c le , a d ip o s e )
p r o te in s y n th e s is
I N L I V E R
in h ib itio n :
lip o ly s is
g ly c o g e n o ly s is
g lu c o n e o g e n e s is
in s u lin r e le a s e in s u lin -in d e p e n d e n t c e lls
p o s tp r a n d ia l h y p e r g lic e m ia
c a r b o h y d r a te s
d ig e s tio n
a b s o b tio n

HYPERGLICEMIAHYPERGLICEMIA
(diabetes mellitus)(diabetes mellitus)
 DiabetesDiabetes - Greek word = to siphon or to- Greek word = to siphon or to
pass thru.pass thru.
 MellitusMellitus - Latin word = sweet or honey.- Latin word = sweet or honey.
 groupgroup of chronic disordersof chronic disorders
 insulininsulin deficiencydeficiency ABSOLUTE/RELATIVEABSOLUTE/RELATIVE
!!! also affects protein and fat metabolism!!! also affects protein and fat metabolism

CLASSIFICATIONCLASSIFICATION
 type 1type 1 DMDM -- autoimmune pancreatic β-cellautoimmune pancreatic β-cell
destruction = absolute insulin deficiency;destruction = absolute insulin deficiency;
 type 2type 2 DMDM - insulin resistance = relative- insulin resistance = relative
insulin deficiency;insulin deficiency;
 ““otherother” specific types of DM” specific types of DM (associated(associated
with identifiable clinical conditions orwith identifiable clinical conditions or
syndromes);syndromes);
 gestationalgestational DMDM - appears or is first- appears or is first
detected during pregnancy.detected during pregnancy.

!!!!!! pre-diabetespre-diabetes
 impaired glucose toleranceimpaired glucose tolerance (IGT)(IGT)
 impaired fasting glucoseimpaired fasting glucose (IFG)(IFG)

ADA diagnosis of DMADA diagnosis of DM
1.1. classic symptomsclassic symptoms of diabetes (polyuria,of diabetes (polyuria,
polydipsia, and unexplained weight loss)polydipsia, and unexplained weight loss) plusplus
random plasma glucose concentrationrandom plasma glucose concentration ≥ 200≥ 200
mg/dL (≥11.1 mmol/L);mg/dL (≥11.1 mmol/L);
oror
2.2. fastingfasting (≥8-hour) plasma glucose concentration(≥8-hour) plasma glucose concentration
≥ 126 mg/dL≥ 126 mg/dL (≥7.0 mmol/L);(≥7.0 mmol/L);
oror
3.3. aa 2-hour postload2-hour postload plasma glucoseplasma glucose
concentrationconcentration ≥ 200≥ 200 mg/dL (≥11.1 mmol/L)mg/dL (≥11.1 mmol/L)
during a 75-g oral glucose tolerance test.during a 75-g oral glucose tolerance test.

ETIOLOGYETIOLOGY
Type 1 diabetesType 1 diabetes
 GeneticGenetic
 EnvironmentalEnvironmental
 AutoimmuneAutoimmune

Type 2 diabetesType 2 diabetes
= relative insulin deficiency= relative insulin deficiency – insulin– insulin
resistanceresistance // inadequate secretoryinadequate secretory
responseresponse
 complexcomplex genetic interactionsgenetic interactions unrelatedunrelated
to HLA genesto HLA genes
 environmental factorsenvironmental factors such assuch as bodybody
weightweight ((obesity)obesity) andand exerciseexercise (lack of(lack of
physical activity)physical activity)..

MODYMODY
 autosomal dominant inheritanceautosomal dominant inheritance
 onset in at least 1 family member youngeronset in at least 1 family member younger
than 25 yearsthan 25 years
 absence of autoantibodiesabsence of autoantibodies
 correction of fasting hyperglycemia withoutcorrection of fasting hyperglycemia without
insulin for at least 2 yearsinsulin for at least 2 years
 absence of ketosis.absence of ketosis.

Type 2 DMType 2 DM pathogenicpathogenic
mechanisms:mechanisms:
 progressive loss of insulin secretory capacityprogressive loss of insulin secretory capacity..
 impaired insulin actionimpaired insulin action ::

impaired mitochondrial function and the resulting accumulationimpaired mitochondrial function and the resulting accumulation
of free fatty acids in insulin-responsive tissues.of free fatty acids in insulin-responsive tissues.

defects of the insulin receptor.defects of the insulin receptor.

defects in “postreceptor” pathwaysdefects in “postreceptor” pathways
 Adipocyte-Derived Hormones and CytokinesAdipocyte-Derived Hormones and Cytokines

LeptinLeptin

AdiponectinAdiponectin

other adipocyte-derived factorsother adipocyte-derived factors (resistin, angiotensinogen,(resistin, angiotensinogen,
interleukin-6, transforming growth factor-β, plasminogeninterleukin-6, transforming growth factor-β, plasminogen
activator inhibitor 1)activator inhibitor 1)

TNF-αTNF-α..

 GlucotoxicityGlucotoxicity..
 LipotoxicityLipotoxicity..
 accelerate hepatic gluconeogenesisaccelerate hepatic gluconeogenesis
 inhibit muscle glucose metabolisminhibit muscle glucose metabolism
 impair pancreatic β-cell function.impair pancreatic β-cell function.

 Type 1 DMType 1 DM produces profound β-cellproduces profound β-cell
failure and insulin deficiency withfailure and insulin deficiency with
secondarysecondary insulin resistance,insulin resistance,
 Type 2 DMType 2 DM is associated with less severeis associated with less severe
insulin deficiency but greaterinsulin deficiency but greater insulininsulin
resistance.resistance.

Glucose homeostasisGlucose homeostasis
Fasting stateFasting state ⇒⇒
↑↑glucagonglucagon ↓↓insulininsulin
↑↑peripheral uptake ofperipheral uptake of
glucoseglucose
↑↑hepatichepatic
glycogenesisglycogenesis
↓↓glycogenolysis andglycogenolysis and
↓↓lypolisis andlypolisis and
ketogenesisketogenesis
Fed stateFed state ⇒↑⇒↑insulininsulin
↓↓peripheral uptakeperipheral uptake
of glucoseof glucose
↑↑ hepatichepatic
↑↑ gluconeogenesisgluconeogenesis
↑↑ lypolisislypolisis
glucoseglucose
glucoseglucose
glucoseglucose
glucoseglucose

diabetes mellitus pathogenesisdiabetes mellitus pathogenesis
N O N -I N S U L I N -D E P E N D E N T
C E L L S
E X C E S S
G L U C O S E D E P O S I T S
I N S U L I N -D E P E N D E N T
C E L L
D E F I C I E N T I N G L U C O S E
G L U C O S E L O S T
I N U R I N E
H Y P E R G L Y C E M I A
A B S O L U T E /R E L A T I V E
L A C K O F I N S U L I N

fasting hyperglycemiafasting hyperglycemia
 mobilization ofmobilization of
substrates from musclesubstrates from muscle
and adipose tissueand adipose tissue
 accelerated hepaticaccelerated hepatic
gluconeogenesis,gluconeogenesis,
glycogenolysis,glycogenolysis,
 impaired removal ofimpaired removal of
endogenous andendogenous and
exogenous fuels byexogenous fuels by
insulin-responsiveinsulin-responsive
tissues.tissues.

 Insuline deficiency -Insuline deficiency - increase lipolysisincrease lipolysis
 GlucagonGlucagon - accelerating hepatic ketogenesis- accelerating hepatic ketogenesis
 Catecholamines growth hormone, and cortisolCatecholamines growth hormone, and cortisol --
increase lipolysis.increase lipolysis.
 type 1 diabetestype 1 diabetes -- converted toconverted to ketoneketone bodiesbodies
 type 2 diabetestype 2 diabetes –– insulin suppress the conversion of freeinsulin suppress the conversion of free
fatty acids to ketonesfatty acids to ketones
!!! The increase in substrate delivery -!!! The increase in substrate delivery - hepatichepatic
steatosissteatosis and severeand severe hhypertriglyceridemiaypertriglyceridemia
(endogenous)(endogenous)..
fasting free fatty acidsfasting free fatty acids

Postprandial HyperglycemiaPostprandial Hyperglycemia
 typetype 11 diabetesdiabetes – insulin deficiency– insulin deficiency
 typetype 22 diabetes -diabetes - delayed insulindelayed insulin
secretionsecretion ++ hepatic insulinhepatic insulin resistanceresistance

thethe liver fails to arrest glucoseliver fails to arrest glucose
productionproduction

fails tofails to appropriately take up glucoseappropriately take up glucose
forfor storagestorage as glycogenas glycogen

glucose uptake by peripheral tissues isglucose uptake by peripheral tissues is
impairedimpaired

Hyperglycaemia
⇓
renal threshold for glucose surpassed
(>170mg/dl)
⇓
GLUCOSURIA
⇓
osmotic diuresis ⇒ POLYURIA
⇓
dehydration ⇒ thirst ⇒ POLYDIPSIA

 Type 1 diabeticType 1 diabetic -- defects in the disposaldefects in the disposal
of ingested proteins and fats as well.of ingested proteins and fats as well.

HyperaminoacidemiaHyperaminoacidemia

Hypertriglyceridemia (exogenousHypertriglyceridemia (exogenous))

ACUTE METABOLICACUTE METABOLIC
COMPLICATIONSCOMPLICATIONS
 diabetic ketoacidosis (DKAdiabetic ketoacidosis (DKA))
 hyperosmolar hyperglycemichyperosmolar hyperglycemic
syndrome (HHS)syndrome (HHS)
 hypoglycemiahypoglycemia

DKADKA
 deficient circulating insulin activitydeficient circulating insulin activity
 excessive secretion of counter-excessive secretion of counter-
regulatory hormones.regulatory hormones.
 hyperglycemia, ketosishyperglycemia, ketosis,, acidosisacidosis
!!!!!! osmotic diuresisosmotic diuresis - dehydration and- dehydration and
electrolyte losselectrolyte loss..

Hyperosmolar HyperglycemicHyperosmolar Hyperglycemic
Syndrome (HHS)Syndrome (HHS)
 patients cannot drink enough liquid topatients cannot drink enough liquid to
keep pace with a vigorous osmotickeep pace with a vigorous osmotic
diuresis.diuresis.

Severe hyperosmolaritySevere hyperosmolarity (>320 mOsm/L)(>320 mOsm/L)

SevereSevere hyperglycemiahyperglycemia (>600 mg/dL).(>600 mg/dL).
 severe acidosis and ketosis aresevere acidosis and ketosis are
generally absentgenerally absent in the HHSin the HHS!!!!!!

HypoglycemiaHypoglycemia
 the earliest subjective warning signs =the earliest subjective warning signs =
aautonomic symptomsutonomic symptoms (sweating, tremor,(sweating, tremor,
palpitations)palpitations)
 Central nervous systemCentral nervous system symptoms and signs =symptoms and signs =
neuroglycopenia:neuroglycopenia:

nonspecific (e.g., fatigue or weakness)nonspecific (e.g., fatigue or weakness)

more clearly neurologic (e.g., double vision, oralmore clearly neurologic (e.g., double vision, oral
paresthesias, slurring of speech, apraxia, personalityparesthesias, slurring of speech, apraxia, personality
change, or behavioral disturbances).change, or behavioral disturbances).

irreversible brain damageirreversible brain damage..
 Hypoglycemic unawareness syndromeHypoglycemic unawareness syndrome

duration of diabetesduration of diabetes

autonomic neuropathyautonomic neuropathy

switched to intensive insulin regimensswitched to intensive insulin regimens..

 Somogyi phenomenonSomogyi phenomenon ––
1.1. normal or increased blood glucose levels at bedtimenormal or increased blood glucose levels at bedtime
2.2. blood glucose drops in early morning hours (2 to 3blood glucose drops in early morning hours (2 to 3
A.M.) usually because nighttime insulin dose is tooA.M.) usually because nighttime insulin dose is too
high.high.
3.3. compensate by producing counterregulatorycompensate by producing counterregulatory
hormones resulting inhormones resulting in hyperglycemia on awakeninghyperglycemia on awakening..
 Dawn phenomenonDawn phenomenon == Decrease in the tissueDecrease in the tissue
sensitivity to insulin between 5 and 8 A.M. -sensitivity to insulin between 5 and 8 A.M. -
prebreakfast hyperglycemiaprebreakfast hyperglycemia
??? release of nocturnal growth hormone??? release of nocturnal growth hormone

CHRONIC DIABETIC COMPLICATIONSCHRONIC DIABETIC COMPLICATIONS
MICROVASCULAR AND NEUROPATHIC COMPLICATIONSMICROVASCULAR AND NEUROPATHIC COMPLICATIONS
 Intracellular glucoseIntracellular glucose

advanced glycationadvanced glycation end productsend products (AGEs)(AGEs)

accelerated polyol pathwayaccelerated polyol pathway

reactive oxygen speciesreactive oxygen species

OthersOthers:: cytokines, angiotensin II, endothelin, growthcytokines, angiotensin II, endothelin, growth
factor stimulation, depletion of basement membranefactor stimulation, depletion of basement membrane
glycosaminoglycansglycosaminoglycans
 Hemodynamic changes in the microcirculationHemodynamic changes in the microcirculation

Diabetic retinopathyDiabetic retinopathy
vascular-neuroinflammatoryvascular-neuroinflammatory
diseasedisease..

breakdown of the blood-retinalbreakdown of the blood-retinal
barrierbarrier (BRB) function and loss of(BRB) function and loss of
retinal neurons.retinal neurons.

activatedactivated macrogliamacroglia and neuronaland neuronal
death.death.

activatedactivated microgliamicroglia exacerbate theexacerbate the
damage.damage.

Diabetic NephropathyDiabetic Nephropathy
 rise in glomerular filtration raterise in glomerular filtration rate..
 glomerular lesionsglomerular lesions
 increased glomerular permeabilityincreased glomerular permeability..
 microalbuminuria (30 to 300 mg/day)microalbuminuria (30 to 300 mg/day)
 diffuse glomerulosclerosisdiffuse glomerulosclerosis
 massive proteinuriamassive proteinuria -- nephrotic syndromenephrotic syndrome
 Systemic hypertensionSystemic hypertension
 progression to ESRDprogression to ESRD..

Diabetic NeuropathyDiabetic Neuropathy
 metabolic factorsmetabolic factors
 vascularvascular
 Nerve growth factorNerve growth factor diminisheddiminished
 Autoimmune mechanismsAutoimmune mechanisms..

 Distal symmetrical (sensorimotor)Distal symmetrical (sensorimotor)
polyneuropathypolyneuropathy
 Acute sensory neuropathyAcute sensory neuropathy
 Focal diabetic neuropathiesFocal diabetic neuropathies
((mononeuropathiesmononeuropathies)) –– painpain
 Entrapment syndromesEntrapment syndromes
 Proximal motor neuropathyProximal motor neuropathy (diabetic(diabetic
amyotrophy)amyotrophy)

Autonomic neuropathyAutonomic neuropathy
 Cardiovascular abnormalitiesCardiovascular abnormalities

preferential dysfunction ofpreferential dysfunction of
parasympathetic fibersparasympathetic fibers

impaired sympathetic vasoconstrictorimpaired sympathetic vasoconstrictor
response and impaired cardiac reflexesresponse and impaired cardiac reflexes..
 Altered gastrointestinal functionAltered gastrointestinal function

hypermotility / hypomotilityhypermotility / hypomotility

GastroparesisGastroparesis

 Genitourinary alterationsGenitourinary alterations

bladder hypotoniabladder hypotonia

Erectile dysfunctionErectile dysfunction
 Abnormal sweat productionAbnormal sweat production

XerosisXerosis..

Distal anhidrosisDistal anhidrosis -- truncal-facial sweatingtruncal-facial sweating

Generalized anhidrosisGeneralized anhidrosis

atherosclerosisatherosclerosis
 lipid abnormalitieslipid abnormalities
 procoagulant state =procoagulant state = accentuatedaccentuated
platelet aggregation and adhesion,platelet aggregation and adhesion,
endothelial cell dysfunctionendothelial cell dysfunction..
 hyperinsulinemiahyperinsulinemia

The diabetic footThe diabetic foot

chronic sensorimotor neuropathychronic sensorimotor neuropathy

vascular diseasevascular disease

abnormal immune functionabnormal immune function

HYPOGLICEMIAHYPOGLICEMIA
 Physiological hypoglycaemia

3-5 hours after ingestion of glucose or during
prolonged fast
 Pathological HYPOGLICEMIA
Whipple’s triad:

LOW BLOOD GLUCOSE below 50 mg/dl

symptoms of hypoglycaemia

symptoms relieved by glucosesymptoms relieved by glucose

Classification:
 Fasting hypoglycaemia

With hyperinsulinemia

Without hyperinsulinemia
 Non-fasting, postprandial or
reactive hypoglycaemia

Fasting hypoglycemia with
hyperinsulinemia
 diabetes
 islet cell tumours
 factitious hypoglycemia
 autoimmune hypoglycaemia
 drugsdrugs

Fasting hypoglycemia without
hyperinsulinemia
 Chronic renal impairment

Decreased renal gluconeogenesis

impaired hepatic glycogenolysis and gluconeogenesis
!!!

increased insulin half-life due to decreased renal
degradation

exaggerated glucose-induces insulin secretion

severe liver disease =
hepatogenous hypoglycaemia
 deficient caloric intake and exercise-
induced hypoglycaemia

septicaemiasepticaemia
early phase - hyperglycemiaearly phase - hyperglycemia
• decrease in insulin-stimulated phosphorylation ofdecrease in insulin-stimulated phosphorylation of
insulin receptorinsulin receptor
• increased clearance of insulinincreased clearance of insulin
• increased production of corticosteroids.increased production of corticosteroids.
late phase – hypoglycemialate phase – hypoglycemia
• cytokinescytokines from macrophages stimulates insulinfrom macrophages stimulates insulin
secretionsecretion
• direct hypoglycemic effect ofdirect hypoglycemic effect of endotoxinsendotoxins (inhibit(inhibit
gluconeogenesis)gluconeogenesis)
• association ofassociation of renal failurerenal failure..

 non-islet cell tumours:

Increased uptake of glucose to tumors

reduced production of glucose

reduced gluconeogenesis due to weight loss

produce peptides with insulin-like activity

cytokines release ? (IGF-2, TNFα)

 drugs :

Salicylates

non-selective beta-blockers
 endocrine insufficiency

hypopituitarism

Addison’s disease

isolate GH or ACTH deficiency

Reactive hypoglycaemia
 Organic causes may lead to rapid emptying of
gastric contents
 Type 2 diabetes mellitus
 Alcohol

potentates the hypoglycaemic effect of insulin

potentates the insulin-stimulating effect of glucose
 Idiopathic
 Inborn errors of metabolism

Disorders of carbohydrates metabolism (galactosemia,
hereditary fructose intolerance….)

Disorders of amino acid metabolism (maple syrup urine
disease….)

Disorders of fatty acid metabolism (systemic carnitine
deficiency….)

The metabolism of glucose

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