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Carbohydrate Proteins
Fats
Most common energy sources
Carbohydrates
Fats
Most common energy
sources
Proteins
Gasoline for human being
Glucose (Carbohydrate)
Fatty acids (Fats)
What is a Carbohydrate?
Carbohydrates are compounds which have the
following basic composition:
I
(CH2O)n or H - C - OH
I
Classified as –
Monosaccharides
Disaccharides
Oligosaccharides
Polysaccharides
Simple Sugars:Mono and
Disaccharides
Monosaccharides – single sugar unit
Glucose
Found in fruits, vegetables, honey
used for energy
Fructose
“fruit
sugar”
Found in fruits, honey, corn syrup
Galactose
Found as part of lactose in milk
Disaccharides – two linked
sugar units
Sucrose: glucose + fructose
“table sugar”
Made from sugar cane and sugar
beets
Lactose: glucose + galactose
“milk sugar”
Found in milk and dairy products
Maltose: glucose + glucose
Found in germinating cereal grains
Product of starch breakdown
Complex
Carbohydrates
Oligosaccharides
driedbeans, peas, lentils
Rafinose (gal-glu-fru)
Stachyose (gal-gal-gal-fru)
Metabolized by intestinal bacteria
Gaseous effects
Complex
Carbohydrates
Polysaccharides
contain 100’s or 1000’s of
monosaccharide units
starch-digestible
fiber-indigestible
Glycogen
Glycogen
Importance
Stored form of glucose.
Major sites – Muscles and Liver; 75% is stored in
muscles.
Liver: major site for glycogen synthesis
~10% of wet weight of liver
Muscles
Glycogen < 1% weight
Used as energy when body requires energy.
Important for “instant” energy
Glycogen Storage
Skeletal muscle
Function: serve as fuel reserve for synthesis
of ATP during muscle contraction
Liver
Function: maintain blood glucose
concentration in times of fasting
Also known as
a-glucosidase
enzymes
Metabolism of Carbohydrates
Glycolysis Glycogenesis
Gluconeogenesis Glycogenolysis
Glycolysis (glucose pyruvate)
Pancreas: Islet of
Langerhans (α , β , δ )
S S
S S
HOOC
S S
How insulin is
synthesized?
Proinsulin
NH2
S S
S S
HOOC
S S
How insulin is
synthesized?
Insulin
HOOC NH2 β -
chain
S S
S S
HOOC NH2 α -
S S chain
C - peptide ESR11-08
Role of C-Peptide
Insulin is difficult to measure
Half-life is only 5 mins
Rapidly inactivated by various enzymes.
C-Peptide has 30 mins half life
Synthesized in equimolar conc to that of
insulin
Determines amount of insulin secreted
from b-cell
How insulin is secreted?
Insulin is secreted in 2 phases –
1. First phase
Sharp peak
Within 3-5 mins of glucose intake
Completed within 10 mins
Release of mature granules.
2. Second phase
Release of secretory
granules that are
mobilized within the
beta cell for release.
Granules contain newly
synthesized insulin.
Second Phase helps to
attain normoglycemia.
Insulin – the “hormone of plenty”
Muscles Liver
Glucose Glycogenolysis
Uptake
Gluconeogenesis
Adipose cells
Glycolysis
Glycogenesis Lipogenesis
K+ Depolarization
Voltage
ATP
dependent Ca+
sensitive K+ +
channels
channels
Binds and open
closes
Ca++
Glucose ATP
Secretary
granules
GLUT-2
Insulin
High
Glucose
Insulin
Insulin
Receptor
Seri
es o
f e nz
reac
tion
GLUT 4
Mode of action of Insulin
Glucose
Insulin enters
Insulin GLUT-4
Receptor
Translocation
of GLUT-4
Series of
reaction
Glucose
Glycogen Glycolysis
Mode of action of insulin
Sources of blood glucose in the various nutritional states
40 Exogenous
(glucose
Glucose 30 from diet)
glucose from
Used gluconeogenesis
g/hr glucose from (lactate + amino acids) glucose from
20 liver glycogen gluconeogenesis
(mostly lactate)
10
0
4 8 12 16 2 7 42
HOURS DAYS
Hyperglycemia & Hypoglycemia
Hyperglycemia – too
little insulin
Insulin
Non esterified Fatty acid (NEFA or FFA)
Hence insulin -
•Decreases lipolysis
•Increases lipogenesis
•Decreases ketoacidosis
Insulin on Protein metabolism
Amino acid
Insulin
Protein
Insulin –
•Increases protein synthesis
•Decreases proteolysis
Summary of insulin action
Increases –
Glucose uptake
Glycolysis
Glycogenesis
Lipogenesis
Protein synthesis
Decreases –
•Gluconeogenesis
•Glycogenolysis
•Lipolysis
•Ketogenesis
•Proteolysis
Diabetes Mellitus
Disease, Pathogenesis
& Management
Definition
A group of metabolic disorders
comprising of abnormal carbohydrate,
fat and protein metabolism and
characterized by chronic or persistence
hyperglycemia
Due to lack of insulin hormone
OR
Improper insulin secretion
Risk Factors for Diabetes
Family history of diabetes
Obesity (> 20% over desired body weight or BMI > 27 kg/m2
Age > 45 years
Sedentary life style
Some ethnic groups ( Indians, African-Americans and native
Americans, asian americans)
Gestational diabetes or delivering a baby weighing more than 9
pounds (4kg or more)
High blood pressure ( > 140/90mmHg)
High blood levels of triglycerides (> 250mg/dl)
low HDL cholesterol level (<35mg/dl)
Symptoms of diabetes
Frequent urination - Polyuria
Excessive thirst - Polydypsia
Excessive hunger - Polyphagia
Fatigue
Weight loss
Blurred vision.
Gestational diabetes.
Type-1 Diabetes mellitus
Abnormal
Insulin β -cell
resistance function
Type 2 diabetes
Insulin resistance
Healthy
600
500
400
300
200
100
-20 -10 0 10 20 30
Years of diabetes
Hyperglycemia
Types of Diabetes Type-2
Obese
Very high degree of insulin resistance
compared to b-cell impairment
Non-obese
Very high degree of b-cell impairment
compared to insulin resistance
Diagnosis of Type-2
Diabetes
FPG (Fasting plasma glucose test)
Normal value 4 - 6%
Acute complications
Diabetes Ketoacidosis (DKA)
Non-ketotic hyperosmolar state (NKHS)
Chronic complications
Vascular
Non-vascular
Diabetic Ketoacidosis
(DKA)
Life threatening complication in Type-1 DM or
patients with lack of insulin
Inadequate insulin
Coma or death
Diabetic Ketoacidosis
(DKA)
Symptoms are –
Nausea and vomiting.
Thirst / polyuria.
Abdominal pain.
Altered mental function.
Shortness of breath.
Treatment – Insulin
injection
Non-Ketotic Hyperosmolar
State (NKHS)
reported in all age groups, but it most frequently
affects older patients with type 2 diabetes
initiating event in hyperosmolar hyperglycemic state is
glucosuric diuresis
Decreased intravascular volume or underlying renal
disease decreases the glomerular filtration rate,
causing the glucose level to increase.
The loss of more water than sodium leads to
hyperosmolarity
Non-Ketotic Hyperosmolar
State (NKHS)
Symptoms are –
• Polyuria.
• Orthostatic hypotension.
• Neurological symptoms like - altered mental status,
lethargy, seizure and possibly coma.
Treatment
1. Vigorous intravenous rehydration,
2. Electrolyte replacement
3. Administration of intravenous insulin,
Chronic Complications
Vascular
Microvascular
Retinopathy
Neuropathy
Nephropathy
Marcovascular
Cardiovascular disease
Cerebrovascular disease
Peripheral vascular disease
Layers of blood vessels
Hyperglycemia damages only a particular subset of
cell types:
capillary endothelial cells in the retina,
mesangial cells in the renal glomerulus,
and neurons and Schwann cells in peripheral
nerves.
AGE pathway
PKC pathway
Hexosamine pathway
PAI-1
Microvascular
Complications
Retinopathy
Leading cause of
blindness
Starts with a small areas
of balloon-like swelling Hemorrhages in non-proliferative diabetic
in the retina's tiny blood retinopathy
vessels.
As the disease
progresses, blood
vessels that nourish the
retina are blocked.
1. Peripheral Neuropathy
• Nerve damage in the feet can result in a loss of foot
sensation, increasing risk of foot problems. Symptoms
include –
• Tingling
• Numbness (severe or long-term numbness can become
permanent)
• Burning
Microvascular
Complications
Neuropathy
2. Autonomic Neuropathy
Autonomic neuropathy most often affects the digestive system,
especially the stomach, blood vessels, urinary system, and sex
organs. Symptoms can be –
Unstable
Variant or Prinzmetal’s
Heart attack
Death of muscle tissue
due to lack of oxygen
Macrovascular
Complications
Cardiovascular
complications
Manageme
nt
Life Style Modifications
Drug Therapy
Drugs
Nitrates
Beta blockers
Calcium channel blockers
Potassium channel openers
Metabolic modifier
Macrovascular
Complications
Cardiovascular
complications
Surgical Procedures
• Bypass surgery
• Balloon angioplasty
Macrovascular
Complications
Cardiovascular
complications
Heart Failure
Inability of the heart to pump sufficient blood to meet the
body’s metabolic requirement
Transient Ischemic
Attack (TIA)
A brain disorder caused by
temporary
disturbance of blood supply to an
area of the brain, resulting in a
sudden, brief decrease in brain
Macrovascular
Complications
Peripheral vascular disease
• Blocking of an artery in
the peripheral region of the
body
• Major cause -
atherosclerosis
Non Vascular
Complications
•Galucoma, Cataract
•Diabetic foot ulcer
•Gastroparesis
•Sexual dysfunction
•Skin changes
Biochemical mechanism
of the development of
diabetic complications
Hypothesis 1
Damage to cells
Hypothesis 2
Glycation
Increased glucose level
Oxidative stress
High glucose
Polyol Pathway
Hyperglycemia
Cellular damage
Management of
Diabetes Type-2
Goals
Immediate Goals:
Goals to stabilize the blood
sugar
Long-term goals:
To prolong life,
Relieve symptoms, and
Prevent long-term complications
Treatment Modalities
Pharmacological therapy.
Importance of achieving
tight glycemic control
Variouslandmark studies have confirmed that by
decreasing glucose level there is a significant
reduction in risk of microvascular and
macrovascular complications.
Intensive Lifestyle
Placebo Intervention Metformin
(n = 1082) (n = 1079) (n = 1073)
Primary failure
No response with a drug given for the first
time
Secondary failure
Gradual lose of action of a drug when
used for a prolonged period. E.g.,
Sulfonylureas.