CARBOHYDRATES METABOLISM DISORDERS

GLUCOSE METABOLISM

 the cornerstone of life  neurons are especially dependent on glucose  regulatory mechanisms:  hyperglycemic hormones = glycogenolysis, gluconeogenesis  hypoglycemic hormone = insulin

liver storage glycogen carbohydrates digestion absobtion postprandial hyperglicemia insulin release insulin-independent cells glucose moves into insulin-dependent cells (muscle, adipose) protein synthesis IN LIVER inhibition: lipolysis glycogenolysis gluconeogenesis

HYPERGLICEMIA

(diabetes mellitus)



Diabetes pass thru.

- Greek word = to siphon or to



Mellitus - Latin word = sweet or honey.



group of chronic disorders



insulin deficiency ABSOLUTE/RELATIVE !!! also affects protein and fat metabolism

CLASSIFICATION



type 1 DM

autoimmune pancreatic β-cell destruction = absolute insulin deficiency; 

type 2 DM

- insulin resistance = relative insulin deficiency; 

“ other ” specific types of DM

(associated with identifiable clinical conditions or syndromes); 

gestational DM

- appears or is first detected during pregnancy.

!!! pre-diabetes



impaired glucose tolerance (IGT)



impaired fasting glucose (IFG)

ADA diagnosis of DM

1.

or

classic symptoms of diabetes (polyuria, polydipsia, and unexplained weight loss)

plus

random plasma glucose concentration ≥ 200 mg/dL (≥11.1 mmol/L);

2.

fasting (≥8-hour) plasma glucose concentration ≥ 126 mg/dL (≥7.0 mmol/L);

or

3.

a 2-hour postload concentration ≥ 200 plasma glucose mg/dL (≥11.1 mmol/L) during a 75-g oral glucose tolerance test.

ETIOLOGY

Type 1 diabetes



Genetic



Environmental



Autoimmune

Type 2 diabetes

= relative insulin deficiency resistance

– insulin /

inadequate secretory response

 complex

genetic interactions

unrelated to HLA genes 

environmental factors

weight

(

obesity)

such as

body

and exercise (lack of

physical activity)

.

MODY

 autosomal dominant inheritance  onset in at least 1 family member younger than 25 years  absence of autoantibodies  correction of fasting hyperglycemia without insulin for at least 2 years  absence of ketosis.

  

Type 2 DM

pathogenic mechanisms:

progressive loss of insulin secretory capacity

.   

impaired insulin action

: impaired mitochondrial function and the resulting accumulation of free fatty acids in insulin-responsive tissues.

defects of the insulin receptor. defects in “postreceptor” pathways    

Adipocyte-Derived Hormones and Cytokines Leptin Adiponectin other adipocyte-derived factors

(resistin, angiotensinogen, interleukin-6, transforming growth factor β, plasminogen activator inhibitor 1)

TNF α

.



Glucotoxicity

.



Lipotoxicity

.

   accelerate hepatic gluconeogenesis inhibit muscle glucose metabolism impair pancreatic β-cell function.



Type 1 DM

produces profound β-cell failure and insulin deficiency with

secondary

insulin resistance, 

Type 2 DM

is associated with less severe insulin deficiency but greater insulin resistance.

Glucose homeostasis Glucose homeostasis

Fasting state  glucagon   insulin insulin Fed state  insulin 

peripheral uptake



peripheral uptake peripheral uptake



peripheral uptake of



peripheral uptake of



hepatic



hepatic



hepatic



hepatic



glycogenolysis and



glycogenolysis and

 

gluconeogenesis

  

gluconeogenesis lypolisis



lypolisis and



lypolisis and

diabetes mellitus pathogenesis

ABSOLUTE/RELATIVE LACK OF INSULIN HYPERGLYCEMIA NON-INSULIN-DEPENDENT CELLS EXCESS GLUCOSE DEPOSITS INSULIN-DEPENDENT CELL DEFICIENT IN GLUCOSE GLUCOSE LOST IN URINE

fasting hyperglycemia

 mobilization of substrates from muscle and adipose tissue  accelerated hepatic

gluconeogenesis, glycogenolysis, ketogenesis

 impaired removal of endogenous and exogenous fuels by insulin-responsive tissues.

fasting free fatty acids

   Insuline deficiency increase lipolysis Glucagon - accelerating hepatic ketogenesis Catecholamines growth hormone, and cortisol increase lipolysis.

 

type 1 diabetes

- converted to

ketone

bodies

type 2 diabetes

– insulin suppress the conversion of free fatty acids to ketones !!! The increase in substrate delivery -

hepatic steatosis

and severe h

ypertriglyceridemia (endogenous)

.

Postprandial Hyperglycemia



type 1

diabetes

– insulin deficiency



type 2

diabetes -

secretion

+

delayed insulin

hepatic insulin

resistance

 the

liver fails to arrest glucose production



fails to

appropriately take up glucose for

storage

as glycogen  glucose uptake by peripheral tissues is impaired

Hyperglycaemia



renal threshold for glucose surpassed (>170mg/dl)



GLUCOSURIA



osmotic diuresis



POLYURIA dehydration

 

thirst



POLYDIPSIA



Type 1 diabetic

- defects in the disposal of ingested proteins and fats as well.



Hyperaminoacidemia



Hypertriglyceridemia (exogenous

)

ACUTE METABOLIC COMPLICATIONS



diabetic ketoacidosis (DKA

) 

hyperosmolar hyperglycemic syndrome (HHS)



hypoglycemia

DKA

 deficient circulating insulin activity  excessive secretion of counter regulatory hormones. 

hyperglycemia, ketosis

,

acidosis

!!! osmotic diuresis - dehydration and electrolyte loss .

Hyperosmolar Hyperglycemic Syndrome (HHS)

 patients cannot drink enough liquid to keep pace with a vigorous osmotic diuresis.  

Severe hyperosmolarity

(>320 mOsm/L)

Severe hyperglycemia

(>600 mg/dL). 

severe acidosis and ketosis are generally absent

in the HHS!!!

Hypoglycemia

 the earliest subjective warning signs = a

utonomic symptoms

(sweating, tremor, palpitations) 

Central nervous system neuroglycopenia:

symptoms and signs =   nonspecific (e.g., fatigue or weakness) more clearly neurologic (e.g., double vision, oral paresthesias, slurring of speech, apraxia, personality change, or behavioral disturbances). 

irreversible brain damage

. 

Hypoglycemic unawareness syndrome

  

duration of diabetes autonomic neuropathy switched to intensive insulin regimens

.

 2.

3.

1.

Somogyi phenomenon

– normal or increased blood glucose levels at bedtime blood glucose drops in early morning hours (2 to 3 A.M.) usually because nighttime insulin dose is too high. compensate by producing counterregulatory hormones resulting in hyperglycemia on awakening .



Dawn phenomenon =

Decrease in the tissue sensitivity to insulin between 5 and 8 A.M. prebreakfast hyperglycemia ??? release of nocturnal growth hormone

CHRONIC DIABETIC COMPLICATIONS

MICROVASCULAR AND NEUROPATHIC COMPLICATIONS

 Intracellular glucose 

advanced glycation end products

(AGEs)  

accelerated polyol pathway reactive oxygen species



Others

: cytokines, angiotensin II, endothelin, growth factor stimulation, depletion of basement membrane glycosaminoglycans  Hemodynamic changes in the microcirculation

Diabetic retinopathy



vascular-neuroinflammatory disease

.



breakdown of the blood-retinal barrier (BRB) function and loss of retinal neurons.



activated

macroglia

death. and neuronal



activated

microglia

damage. exacerbate the

Diabetic Nephropathy



rise in glomerular filtration rate

. 

glomerular lesions



increased glomerular permeability

. 

microalbuminuria (30 to 300 mg/day)



diffuse glomerulosclerosis



massive proteinuria - nephrotic syndrome



Systemic hypertension



progression to ESRD

.

Diabetic Neuropathy



metabolic factors



vascular



Nerve growth factor

diminished 

Autoimmune mechanisms

.



Distal symmetrical (sensorimotor) polyneuropathy



Acute sensory neuropathy



Focal diabetic neuropathies ( mononeuropathies

) – pain 

Entrapment syndromes



Proximal motor neuropathy amyotrophy) (diabetic

Autonomic neuropathy



Cardiovascular abnormalities



preferential dysfunction of parasympathetic fibers



impaired sympathetic vasoconstrictor response and impaired cardiac reflexes

. 

Altered gastrointestinal function

 hypermotility / hypomotility 

Gastroparesis



Genitourinary alterations



bladder hypotonia



Erectile dysfunction



Abnormal sweat production



Xerosis

. 

Distal anhidrosis

-

truncal-facial sweating



Generalized anhidrosis

atherosclerosis



lipid abnormalities



procoagulant state = accentuated platelet aggregation and adhesion, endothelial cell dysfunction

. 

hyperinsulinemia

The diabetic foot



chronic sensorimotor neuropathy



vascular disease



abnormal immune function

HYPOGLICEMIA



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 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



drugs

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

septicaemia

early phase - hyperglycemia

• decrease in insulin-stimulated phosphorylation of insulin receptor • • increased clearance of insulin increased production of corticosteroids.

late phase

•

– hypoglycemia cytokines

secretion from macrophages stimulates insulin • direct hypoglycemic effect of gluconeogenesis)

endotoxins

(inhibit • association of

renal 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 gastric contents may lead to rapid emptying of 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….)