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….)