DIABETES
INTRODUCTION
- Tendency for chronic hyperglycemia
- Either due to
● Reduced insulin production [Type I DM, LADA- Latent
Autoimmune Diabetes of Adults]
● Resistance to the action of insulin [Type II DM,
MODY-Maturity Onset Diabetes in Young ]
● its combination [Gestational DM]
● Secondary DM [drug induced - beta blockers which blocks
receptors in pancreas, thiofide] [Cushing syndrome -
cortisol → catabolism of protein and lipolysis of lipids →
aminoacid and free fatty acids released and supplied to
liver → gluconeogenesis → glucose] [acromegaly]
- All carbohydrate, protein and lipid metabolisms are disturbed
CAUSES
- Lifestyle changes : unhealthy nutrition, processed food, sugars;
obesity
- Physical activity reduced
- Increased lifespan and more people in older age
- Stress of modern life
COMPLICATIONS
- Vascular problems
2 types:
1. Macrovascular complication / Macroangiopathy
● Coronary Artery Disease
● Cerebro Vascular Accidents
● Peripheral Vascular Disease
● Diabetic Reno Vascular Disease
2. Microvascular complication / Microangiopathy
Basement membrane of capillaries become thick and
cracked because of the alteration of its proteins
→ leakage of blood
● Diabetic Retinopathy
● Diabetic Nephropathy
● Diabetic Neuropathy
- Other complications
● Gastropathy
● Cataract and Glaucoma
● Even damage to muscles and nerves supplying eyes
● More prone to infections anywhere in the body
● Otitis externa, otitis media, vestibular nerve damage,
sensory neuronal deafness
● Periodontal disease
DIABETIC NEUROPATHY
FORMS
- Peripheral neuropathy
● Most commonly in lower limbs. The sensory neurons
(mostly) and motor neurons undergo dysfunction.
● Symmetrical polyneuropathy(mcc); some develop
mononeuropathy → isolated nerve damage;
● Parasthesia
● Tingling, pin & needle sensation
● Later involves arms
● Also called Gloves and Stocking disease
● Also contribute to Diabetic Foot Disease
- Autonomic Neuropathy
● For eg: if ANS to heart is damaged → beat-to-beat
variability reduced, orthostatic hypotension (postural
hypotension)
● Eg : if vagus nerve is affected → GIT motility abnormal -
gastroparesis
● Eg : if ANS to urogenital system damaged → urinary
retention, impotence
GLUCOSE REGULATION IN HEALTHY
FBS : 60 - 100 mg/dL
Within 2 hrs of taking food, PPBS should be <140 mg/dL
RBS <200 mg/dL
Levels more than normal → toxicity
Why the glucose in blood be maintained at normal ?
- The metabolism of certain organs solely depend on glucose like
CNS, neurons, retina, germinal epithelium (testes / ovaries)
How Hyperglycemia becomes dangerous?
- Extracellular fluid become hyperosmotic → fluid drains from
the cells → dehydrated cells → do not perform optimally
- Kidneys: heavy filtered load of glucose → not all of the glucose
can be reabsorbed → these glucose are excreted in urine →
glycosuria → diuresis → polyuria → dehydration → thirst
centre in hypothalamus activated → polydipsia → weight loss;
Glycosuria → energy loss → increased appetite;
Water passes rapidly through the nephrons due to osmotic effect
of glucose → proper reabsorption of electrolyte by epithelium
destroyed → electrolyte imbalance
- Chronic effect:
● Glucose is directly toxic to endothelium by dehydrating
the cells with every hyperglycemic peak
● Glucose reacts to proteins producing - AGE - Advanced
Glycation End Products
● Thus Macrovascular diseases (atheromatic plaques in large
and medium sized vessels) which appears pathologically
as widespread aggressive rapidly developing
Atherosclerotic Disease which manifest as CAD, MI,
CVA, PVD, RVD
● Microvascular diseases also develop which manifest as
retinopathy. neuropathy, nephropathy,
How hypoglycemia effect body?
- Some tissues that preferentially use glucose for function
HORMONES
HORMONES THAT MAINTAIN GLUCOSE LEVEL FROM
FALL
- Glucagon
- Epinephrine
- Norepinephrine
- Cortisol
- Growth hormone
HORMONES THAT MAINTAIN GLUCOSE LEVEL FROM
RAISING
- Insulin
- C Peptide
- Amylin
Insulin
Insulin receptors are found in the cell membrane itself.
Beta units of insulin receptor have intrinsic tyrosine kinase activity →
Insulin receptor substrate - IRS - then gets attached to the
phosphorylated insulin receptor → leads to phosphorylation of IRS →
leads to many signalling pathways →
(1) PI 3- K – AKT pathway
binds to protein PI 3- K → Protein Kinase B/PKB / AKT →
phosphorylation of many proteins leading to activation of
phosphatase → remove phosphate from different enzymes (de
phosphorylation) → activation of the enzymes → alter
metabolic pathways
(2) Ras - MAP-K pathway
SOS interact with the protein Ras protein → act with enzymes
Map kinases/ MAP -K → signal nucleus and genetic system →
alter the synthesis of enzyme
SYMPTOMS
- HYPOGLYCEMIA
● Glycopenic CNS symptoms - Altered behaviour -
irritability, confusion, delirium, seizures, coma, death
● Autonomic manifestations of hypoglycemia - Glucose
sensors in hypothalamus are activated → sympathetic and
parasympathetic overflow
Adrenergic problems: tremors, palpitations, anxiety
Cholinergic problems: sweating, hunger, paresthesia
IN FED STATE
Small intestine → release incretins - GLP 1 and GIP →
● acts on beta cells of Islets of Langerhans → amplify the insulin
release along with glucose stimuli
● Act on stomach → reduce the motor activity of stomach →
helps in better absorption of chyle
● Act on hypothalamus → stimulate satiety centre → satiety
Glucose enters into beta cells through Glut-2 receptors.
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Glucose is converted into Glu-6-phosphate by Glucokinase
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Glycolysis
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Pyruvate
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Kreb cycle
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ATP levels rise in cell
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ATP blocks K+ channels in cell membrane
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Insulin is released
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Via portal circulation reaches liver
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Glucose is absorbed, utilised and stored in the liver
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Blood leaving liver has less glucose
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