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CARBOHYDRATECARBOHYDRATESS METABOLISM METABOLISM DISORDERSDISORDERS
GLUCOSE METABOLISMGLUCOSE METABOLISM
the cornerstone of lifethe cornerstone of life neurons are especially dependent on neurons are especially dependent on
glucoseglucose regulatory mechanisms:regulatory mechanisms:
hyperglycemic hormones = glycogenolysis, hyperglycemic hormones = glycogenolysis, gluconeogenesis gluconeogenesis
hypoglycemic hormone = insulinhypoglycemic hormone = insulin
l iv er s to r a g eg lyco g e n
g lu c o se m o v es in toin su lin -d e p en d e n t ce lls
(m u sc le , a d ip o se )
p r o te in syn th e s isIN L IV E R
in h ib it io n :lip o lys is
g lyco g e n o lys isg lu c o n eo g e n e s is
in su lin re lea se in su lin -in d ep e n d e n t c e lls
p o stp r a n d ia l h yp e rg lic em ia
c a r b o h yd r a te sd ig e st io na b so 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 disorders of chronic disorders
insulin insulin deficiencydeficiency ABSOLUTE/RELATIVEABSOLUTE/RELATIVE
!!! also affects protein and fat metabolism!!! also affects protein and fat metabolism
CLASSIFICATIONCLASSIFICATION
type 1 type 1 DM DM -- autoimmune pancreatic β-cell autoimmune pancreatic β-cell destruction = absolute insulin deficiency; destruction = absolute insulin deficiency;
type 2 type 2 DM DM - 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 or with identifiable clinical conditions or syndromes); syndromes);
gestationalgestational DM DM - 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 glucose impaired 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 concentration random 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. a a 2-hour postload2-hour postload plasma glucose plasma glucose concentration concentration ≥ 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.
ETIOLOGY ETIOLOGY
Type 1 diabetesType 1 diabetes GeneticGenetic EnvironmentalEnvironmental AutoimmuneAutoimmune
Type 2 diabetesType 2 diabetes
= relative insulin deficiency= relative insulin deficiency – insulin – insulin resistanceresistance / / inadequate secretory inadequate secretory responseresponse
complex complex genetic interactionsgenetic interactions unrelated unrelated to HLA genesto HLA genes
environmental factorsenvironmental factors such as such as body body weightweight ( (obesity)obesity) and and exerciseexercise (lack of (lack of physical activity)physical activity). .
MODYMODY
autosomal dominant inheritance autosomal dominant inheritance onset in at least 1 family member younger onset in at least 1 family member younger
than 25 yearsthan 25 years absence of autoantibodiesabsence of autoantibodies correction of fasting hyperglycemia without correction 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 pathogenic pathogenic mechanisms:mechanisms:
progressive loss of insulin secretory capacityprogressive loss of insulin secretory capacity. . impaired insulin actionimpaired insulin action : :
impaired mitochondrial function and the resulting accumulation impaired 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” pathways defects 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, plasminogen interleukin-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-cell produces profound β-cell failure and insulin deficiency with failure and insulin deficiency with secondarysecondary insulin resistance, insulin resistance,
Type 2 DMType 2 DM is associated with less severe is associated with less severe insulin deficiency but greater insulin deficiency but greater insulin insulin resistance.resistance.
Glucose homeostasisGlucose homeostasis
Fasting state Fasting state glucagon glucagon insulin insulin
peripheral uptake ofperipheral uptake ofglucoseglucose
hepatichepaticglycogenesisglycogenesis
glycogenolysis andglycogenolysis andgluconeogenesisgluconeogenesis
lypolisis andlypolisis andketogenesisketogenesis
Fed state Fed state insulin insulin
peripheral uptakeperipheral uptakeof glucoseof glucose
hepatic hepaticglycogenesisglycogenesis
gluconeogenesis gluconeogenesis
lypolisis lypolisis
Glucose homeostasisGlucose homeostasis
Fasting state Fasting state glucagon glucagon insulin insulin
peripheral uptake ofperipheral uptake ofglucoseglucose
hepatichepaticglycogenesisglycogenesis
glycogenolysis andglycogenolysis andgluconeogenesisgluconeogenesis
lypolisis andlypolisis andketogenesisketogenesis
Fed state Fed state insulin insulin
peripheral uptakeperipheral uptakeof glucoseof glucose
hepatic hepaticglycogenesisglycogenesis
gluconeogenesis gluconeogenesis
lypolisis lypolisis
Glucose homeostasisGlucose homeostasis
Fasting state Fasting state glucagon glucagon insulin insulin
peripheral uptake ofperipheral uptake ofglucoseglucose
hepatichepaticglycogenesisglycogenesis
glycogenolysis andglycogenolysis andgluconeogenesisgluconeogenesis
lypolisis andlypolisis andketogenesisketogenesis
Fed state Fed state insulin insulin
peripheral uptakeperipheral uptakeof glucoseof glucose
hepatic hepaticglycogenesisglycogenesis
gluconeogenesis gluconeogenesis
lypolisis lypolisis
Glucose homeostasisGlucose homeostasis
Fasting state Fasting state glucagon glucagon insulin insulin
peripheral uptake ofperipheral uptake ofglucoseglucose
hepatichepaticglycogenesisglycogenesis
glycogenolysis andglycogenolysis andgluconeogenesisgluconeogenesis
lypolisis andlypolisis andketogenesisketogenesis
Fed state Fed state insulin insulin
peripheral uptakeperipheral uptakeof glucoseof glucose
hepatic hepaticglycogenesisglycogenesis
gluconeogenesis gluconeogenesis
lypolisis lypolisis
Glucose homeostasisGlucose homeostasis
Fasting state Fasting state glucagon glucagon insulin insulin
peripheral uptake ofperipheral uptake ofglucoseglucose
hepatichepaticglycogenesisglycogenesis
glycogenolysis andglycogenolysis andgluconeogenesisgluconeogenesis
lypolisis andlypolisis andketogenesisketogenesis
Fed state Fed state insulin insulin
peripheral uptakeperipheral uptakeof glucoseof glucose
hepatic hepaticglycogenesisglycogenesis
gluconeogenesis gluconeogenesis
lypolisis lypolisis
diabetes mellitus pathogenesisdiabetes mellitus pathogenesis
N O N -IN S U L IN -D E P E N D E N TC E L L S
E X C E S SG L U C O S E D E P O S IT S
IN S U L IN -D E P E N D E N TC E L L
D E F IC IE N T IN G L U C O S E
G L U C O S E L O S TIN U R IN E
H Y P E R G L Y C E M IA
A B S O L U T E /R E L A T IV EL A C K O F IN S U L IN
fasting hyperglycemiafasting hyperglycemia mobilization of mobilization of
substrates from muscle substrates from muscle and adipose tissueand adipose tissue
accelerated hepatic accelerated hepatic gluconeogenesis, gluconeogenesis, glycogenolysis, glycogenolysis, ketogenesisketogenesis
impaired removal of impaired removal of endogenous and endogenous and exogenous fuels by exogenous fuels by insulin-responsive insulin-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 to converted to ketoneketone bodies bodies type 2 diabetestype 2 diabetes –– insulin suppress the conversion of free insulin suppress the conversion of free
fatty acids to ketonesfatty acids to ketones
!!! The increase in substrate delivery - !!! The increase in substrate delivery - hepatic hepatic steatosissteatosis and severe and severe hhypertriglyceridemia ypertriglyceridemia (endogenous)(endogenous)..
fasting free fatty acidsfasting free fatty acids
Postprandial HyperglycemiaPostprandial Hyperglycemia
type type 11 diabetes diabetes – insulin deficiency – insulin deficiency type type 22 diabetes - diabetes - delayed insulin delayed insulin
secretionsecretion + + hepatic insulin hepatic insulin resistanceresistance the the liver fails to arrest glucose liver fails to arrest glucose
productionproduction fails tofails to appropriately take up glucose appropriately take up glucose
for for storagestorage as glycogen as glycogen glucose uptake by peripheral tissues is glucose 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 disposal defects in the disposal
of ingested proteins and fats as well.of ingested proteins and fats as well. HyperaminoacidemiaHyperaminoacidemia
Hypertriglyceridemia (exogenousHypertriglyceridemia (exogenous))
ACUTE METABOLIC ACUTE METABOLIC COMPLICATIONSCOMPLICATIONS
diabetic ketoacidosis (DKAdiabetic ketoacidosis (DKA)) hyperosmolar hyperglycemic hyperosmolar hyperglycemic
syndrome (HHS) syndrome (HHS) hypoglycemiahypoglycemia
DKADKA
deficient circulating insulin activity deficient 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 Hyperglycemic Hyperosmolar Hyperglycemic Syndrome (HHS)Syndrome (HHS)
patients cannot drink enough liquid to patients cannot drink enough liquid to keep pace with a vigorous osmotic keep pace with a vigorous osmotic diuresis. diuresis. Severe hyperosmolaritySevere hyperosmolarity (>320 mOsm/L) (>320 mOsm/L) Severe Severe hyperglycemiahyperglycemia (>600 mg/dL). (>600 mg/dL).
severe acidosis and ketosis are severe acidosis and ketosis are generally absentgenerally absent in the HHS in the HHS!!!!!!
HypoglycemiaHypoglycemia the earliest subjective warning signs = the earliest subjective warning signs =
aautonomic symptoms utonomic 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, oral more clearly neurologic (e.g., double vision, oral
paresthesias, slurring of speech, apraxia, personality paresthesias, 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 3 blood glucose drops in early morning hours (2 to 3 A.M.) usually because nighttime insulin dose is too A.M.) usually because nighttime insulin dose is too high. high.
3.3. compensate by producing counterregulatory compensate by producing counterregulatory hormones resulting in hormones resulting in hyperglycemia on awakeninghyperglycemia on awakening..
Dawn phenomenonDawn phenomenon == Decrease in the tissue Decrease 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 products end products (AGEs) (AGEs) accelerated polyol pathwayaccelerated polyol pathway reactive oxygen speciesreactive oxygen species
OthersOthers: : cytokines, angiotensin II, endothelin, growth cytokines, angiotensin II, endothelin, growth factor stimulation, depletion of basement membrane factor stimulation, depletion of basement membrane glycosaminoglycansglycosaminoglycans
Hemodynamic changes in the microcirculationHemodynamic changes in the microcirculation
Diabetic retinopathyDiabetic retinopathy
vascular-neuroinflammatory vascular-neuroinflammatory diseasedisease. . breakdown of the blood-retinal breakdown of the blood-retinal
barrierbarrier (BRB) function and loss of (BRB) function and loss of retinal neurons. retinal neurons.
activated activated macrogliamacroglia and neuronal and neuronal death. death.
activated activated microgliamicroglia exacerbate the exacerbate 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 proteinuria massive proteinuria -- nephrotic syndrome nephrotic syndrome Systemic hypertension Systemic hypertension progression to ESRDprogression to ESRD. .
Diabetic NeuropathyDiabetic Neuropathy
metabolic factorsmetabolic factors vascularvascular Nerve growth factorNerve growth factor diminished diminished Autoimmune mechanismsAutoimmune mechanisms..
Distal symmetrical (sensorimotor) Distal symmetrical (sensorimotor) polyneuropathypolyneuropathy
Acute sensory neuropathy Acute sensory neuropathy
Focal diabetic neuropathies Focal diabetic neuropathies ((mononeuropathiesmononeuropathies) ) –– pain pain
Entrapment syndromesEntrapment syndromes
Proximal motor neuropathyProximal motor neuropathy (diabetic (diabetic amyotrophy)amyotrophy)
Autonomic neuropathyAutonomic neuropathy
Cardiovascular abnormalitiesCardiovascular abnormalities preferential dysfunction of preferential dysfunction of
parasympathetic fibersparasympathetic fibers impaired sympathetic vasoconstrictor impaired 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 = accentuated accentuated
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 of decrease in insulin-stimulated phosphorylation of
insulin receptor insulin receptor • increased clearance of insulin increased clearance of insulin • increased production of corticosteroids. increased production of corticosteroids.
late phase – hypoglycemialate phase – hypoglycemia• cytokinescytokines from macrophages stimulates insulin from macrophages stimulates insulin
secretion secretion • direct hypoglycemic effect of direct hypoglycemic effect of endotoxinsendotoxins (inhibit (inhibit
gluconeogenesis)gluconeogenesis)• association of association 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, TNF)
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….)