DIABETES MELLITUS

V.VYTHEESHWARAN

BIOCHEMISTRY FOR U, CHENNAI http://biochemistryforu.googlepages.com/home

 DIABETES MELLITUS
• Diabetes mellitus is a chronic disease
due primarily to a disorder of
carbohydrate metabolism, cause of
which is deficiency or diminished
effectiveness of insulin, resulting in
hyperglycemia and glycosuria.
• May also cause secondary changes in
metabolism of proteins, and lipids
leading to grave consequences.
DIABETIC CAPITAL OF
THE WORLD!!!

INDIA
 DIABETES - STAGES
• There are 4 stages in
diabetes:
– Pre-diabetics
– Suspected diabetes

– Chemical/Latent
diabetes
– Overt diabetes
 DIABETES - TYPES
• There are three major forms of
diabetes:

– Type I Diabetes (IDDM) (Juvenile onset)

– Type II Diabetes (NIDDM) (Maturity onset)
– Gestational Diabetes

• Secondary forms:
– Pancreatic Diabetes
– Hormonal Diabetes
– Iatrogenic Diabetes
 DIABETES MELLITUS
FACTORS
• Heredity
• Auto-immunity
• Infections
• Obesity
• Diet
• Insulin antagonism
 PATHOPHYSIOLOGY
• Pancreas is composed of cells scattered
throughout called the islets of Langerhans
• Two types of cells are important to glucose
control
• Alpha cells- produce glucagon
– Hormone that acts opposite of insulin
– Causes release of glucose from cell storage
• Beta cells- produce insulin
– Allows body cells to use and store carbohydrate, fat,
and protien
 INSULIN
• Insulin is a protein made of 2 chains- alpha and
beta
• Preproinsulin is produced initially
– Precursor molecule that is inactive
– Must be made smaller before becoming active
• Proinsulin
– Precursor that includes alpha and beta chains
– Also has a C-peptide chain
– C-peptide levels are used to measure rate that beta
cells secrete insulin
 INSULIN
• Insulin allows glucose to move into cells to
make energy
• Liver is first major organ to be reached
– Promotes production and storage of glycogen
(glycogenisis)
– Inhibits glycogen breakdown into glucose
(glycogenolysis)
– Increases protein and lipid synthesis
– Inhibits tissue breakdown by inhibiting liver
glycogenolysis (ketogenesis- converts fats to acids) &
gluconeogenisis (conversion of proteins to glucose)
– In muscle, promotes protein and glycogen synthesis
– In fat cells, promotes triglyceride storage
 INSULIN
• Pancreas secretes 40-50 units of insulin
daily in two steps:
– Secreted at low levels during fasting ( basal
insulin secretion
– Increased levels after eating (PP)
– An early burst of insulin occurs within 10
minutes of eating
– Then proceeds with increasing release as
long as hyperglycemia is present
 GLUCOSE HOMEOSTASIS
• Glucose is main fuel for CNS
• Brain cannot make or store, therefore
needs continuous supply
• Fatty acids can be used when glucose is
not available ( triglycerides)
• Need 68-105 mg/dL to support brain
• Decreased levels of glucose, insulin
release is stopped with glucagon released
 GLUCOSE
• Glucagon causes release of glucose from liver
– Liver glucose is made thru glycogenolysis (glucogen
to glucose) &
– Gluconeogenesis
• When liver glucose is not available, lypolysis
occures ( breakdown of fat) OR
• Proteinlysis (breakdown of amino acids)
 ABSENCE OF INSULIN
• Insulin needed to move glucose into
cells.
• Without insulin, body enters a state
of breaking down fats and proteins.
• Glucose levels increase
(hyperglycemia).
 DIABETES - TYPE I

• It results from primary beta cell

destruction leading to absolute
insulin deficiency.
• Also caused by genetic defects of
beta cell; genetic defects in insulin
action; other endocrine and
exocrine dysfunctions; drug
induced; other genetic syndromes
 DIABETES – TYPE I
• Frequency-less
• Commences usually before 15 yrs of age.
• Frequency: Males > than Females.
• Onset-rapid and abrupt
• Speedy Progression to Keto-acidosis and coma
• Usually patients are thin and underweight
• Deficient Insulin: At first Juvenile diabetics produce
more insulin than normal, but the beta-cells soon
become exhausted and patient becomes "overt"
diabetics with atrophied p-cells and practically no
insulin .
• Plasma insulin- It is almost absent. No insulin response
is shown to glucose load.
• Insulin therapy-is necessary for control of these cases.
 DIABETES – TYPE II
• Frequency-more common.
• Occurs in middle aged individuals. More
common in women.
• Onset is insidious
• Usually mild. Ketoacidosis is rare.
• Associated with obesity in 2/3 of cases. Usually
detected during routine check-up of urine.
• Beta cells respond normally. Relative insulin
deficiency may be due to insulin antagonism.
• Plasma levels of insulin may be normal or
raised.
• Oral hypoglycemic agents and diet control are
useful in treatment.
 GESTATIONAL DIABETES
• Gestational diabetes mellitus (GDM) is
defined as any degree of glucose
intolerance with onset or first recognition
during pregnancy.
 GDM – SYMPTOMS
• Glycosuria.
• Elevated blood glucose levels.
• Usually appears between 24-28 weeks
gestation.
• Degree of hyperglycemia is not as severe
as in other types of diabetes.
 SECONDARY DIABETES
• This condition is observed when diabetes occurs
secondary to some diseases.
• Pancreatic diabetes:
– Pancreatitis
– Haemochromatosis
– Malignancy of Pancreas.
• Abnormal concentrations of antagonistic hormones
– Hyperthyroidism
– Hypercorticism: like Cushing’s syndrome
– Hyperpituitarism: like acromegaly
– Increased glucagon activity.
• Iatrogenic
– In genetically susceptible cases, may be precipitated by therapy
like corticosteroids, thiazide diuretics.
 CLINICAL FEATURES AND
BIOCHEMICAL CORRELATIONS
• Polyuria
• Polydypsia
• Polyphagia
• Weakness and fatigue
• Diabetic Ketoacidosis
• Hypercholesterolemia leading to atherosclerosis
• Weight loss
• Hemoconcentration- related to dehydration
• Hypovolemia- decreased blood volume
• Hyperviscosity – thick concentrated blood
• Hypoperfusion- decreased circulation
• Hypokalemia and Hyponatremia
• Kussmaul respirations
 CLINICAL FEATURES AND
BIOCHEMICAL CORRELATIONS
• Polyuria:
– Frequent and excessive urination
– Osmotic diuresis caused by excess glucose in urine
– Water loss can be severe along with sodium,
chloride, and potassium
• Polydipsia:
– Excessive thirst associated with dehyration
• Polyphagia:
– Cells do not receive glucose leading to starvation
which triggers excessive eating
 CLINICAL FEATURES AND
BIOCHEMICAL CORRELATIONS
• Weakness and fatigue
– Due to lack of glucose available for ATP
formation.
• Weight loss
– Catabolism of lipids and proteins as a part of
gluconeogenesis
 CLINICAL FEATURES AND
BIOCHEMICAL CORRELATIONS
• Diabetic Ketoacidosis
– DKA results in altered lipid metabolism.
– increased concentrations of total lipids, cholesterol,
triglycerides, and free fatty acids.
– free fatty acids are shunted into ketone body
formation due to lack of insulin; the rate of
formation exceeds the capacity for their peripheral
utilization and renal excretion leading to
accumulation of ketoacids, and therefore metabolic
acidosis.
 CLINICAL FEATURES AND
BIOCHEMICAL CORRELATIONS

• Hypercholesterolemia & Atherosclerosis

– Abnormal lipid metabolism leading to FFA
and cholesterol biosynthesis.
– Cholesterol deposition - “lead pipe arteries”
 CLINICAL FEATURES AND
BIOCHEMICAL CORRELATIONS
• Kussmaul respirations:
– Excess acids cause increased H+ and CO2
levels
– Stimulate brain to increase rate and depth of
respirations to excrete acid and carbon
dioxide
– Acetone is exhaled thus breath has “fruity”
odor
– Ultimately, pH will drop
• Hypokalemia and Hyponatremia
– Lack of insulin causes depletion of potassium
and sodium
 CHRONIC COMPLICATIONS
• Blood vessels changes
– Macrovascular:
• Coronary heart disease, cerebrovascular accidents; &
peripheral vascular disease
• Major risk factor for CAD, MI
– Microvascular:
• Nephropathy (kidney dysfunction); neruopathy (nerve
dysfunction); & retinopathy (vision problems)
• Blindness is 25 times more common
• Microaneurysms
• Neovascularization- new blood vessels but thin, fragile and
bleed easily
• Male erectile dysfunction (ED)
 DIABETIC RETINOPATHY
• Diabetes results in changes in veins, arteries and
capillaries in the body.
• Risk of developing diabetic retinopathy: damage
occurs to the fragile blood vessels inside the
retina.
• Could develop cataracts (clouding of the naturally
clear lens in the eye).
• May develop glaucoma (a disease of the optic
nerve).
• 2 Forms – Non proliferative Diabetic Retinopathy
(NPDR) and Proliferative Diabetic Retinopathy
(PDR).
 NPDR
• Early stage diabetic retinopathy
• Hard exudates on the central
retina (macula).
• Microaneurysms (small bulges in
blood vessels of the retina that
often leak fluid).
• Retinal hemorrhages (tiny spots of
blood that leak into the retina).
• Macular edema Retina showing NPDR
(swelling/thickening of macula).
• Macular ischemia (closing of
small blood vessels/capillaries).
 PDR
• Later stage diabetic retinopathy
• Vitreous hemorrhage (new,
abnormal blood vessels bleed into
vitreous gel in center of eye,
preventing light rays from reaching
the retina).
• Traction retinal detachment (new,
abnormal blood vessels begin to
shrink and tug on retina; may cause
retina to detach).
• Neovascular glaucoma
(neovascularization occurs in the Retina showing PDR
iris, causing pressure to build up in
the eye, damaging the optic nerve).
 DIABETIC NEPHROPATHY
• Diabetic nephropathy (nephropatia
diabetica), also known as Kimmelstiel-
Wilson syndrome and intercapillary
glomerulonephritis.
• It is a progressive kidney disease caused by
angiopathy of capillaries in the kidney
glomeruli.
• Characterized by nodular
glomerulosclerosis.
 DIABETIC NEPHROPATHY
• Stage 1: Hyperfiltration, or an increase in
glomerular filtration rate (GFR) occurs.
Kidneys increase in size.
• Stage 2: Glomeruli begin to show damage and
microalbuminurea occurs.
• Stage 3: Albumin excretion rate (AER) exceeds
200 micrograms/minute, and blood levels of
creatinine and urea-nitrogen rise. Blood
pressure may rise during this stage.
 DIABETIC NEPHROPATHY
• Stage 4: GFR decreases to less than 75 ml/min,
large amounts of protein pass into the urine, and
high blood pressure almost always occurs. Levels
of creatinine and urea-nitrogen in the blood rise
further.
• Stage 5: Kidney failure, or end stage renal disease
(ESRD). GFR is less than 10 ml/min. The average
length of time to progress from Stage 1 to Stage 4
kidney disease is 17 years for a person with type 1
diabetes. The average length of time to progress
to Stage 5, kidney failure, is 23 years.
 HYPERGLYCEMIC-
HYPEROSMOLAR-NONKETOTIC
SYNDROME AND COMA
• Increased blood osmolarity caused by
hyperglycemia
• Absence of ketosis and higher blood
glucose levels & blood osmolarity
(>800mg/dL) (44.5 mmol/L)
• Other manifestations are more severe
 HHNS
• MI, sepsis, pancreatitis, stroke, some drugs
may cause HHNS
• Clients may have seizures or reversible
paralysis
• Related to residual insulin secretion:
– client secretes just enough insulin to prevent
ketoacidosis, but not hyperglycemia
– Profound diuresis with e-lyte imbalance
– Decreased kidney perfusion leads to decreased urine
output leading to decreased glucose in urine
DIABETIC NEUROPATHY AND
DIABETIC FOOT
• Neuropathy
– Sensory
– Motor
– autonomic
• Regulates sweating and perfusion to the limb
• Loss of autonomic control inhibits
thermoregulatory function and sweating
• Result is dry, scaly and stiff skin that is prone
to cracking and allows a portal of entry for
bacteria
 DIABETIC FOOT
• Loss of protective sensation
• Starts distally and migrates proximally in
“stocking” distribution
• Large fibre loss – light touch and
proprioception
• Small fibre loss – pain and temperature
• Usually a combination of the two.
• Mild form of diabetic foot – Charcot foot
 DIABETIC FOOT
• Mostly affects forefoot ulceration
– Intrinsic muscle wasting – claw toes
– Equinous contracture
• Two mechanisms of Ulceration
– Unacceptable stress few times
• rock in shoe, glass, burn
– Acceptable or moderate stress repeatedly
• Improper shoe ware
• deformity
 DIABETIC FOOT
Wagner’s Classification
2. Intact skin (impending ulcer)
3. Superficial
4. Deep to tendon bone or
ligament
5. Osteomyelitis (Bone marrow
inflammation)
6. Gangrene of toes or forefoot
7. Gangrene of entire foot
TREATMENT PROTOCOLS
METABOLIC CHANGES IN
DIABETES MELLITUS
 LAB DIAGNOSTICS
• Urine tests:
– Ketones
– Renal function
– Glucose
• Blood tests:
– Fasting blood glucose test
– Oral glucose tolerance test
– Glycosylated hemoglobin assays
– Glycosylated serum proteins and albumin
 URINE TESTS
• Ketones:
– Waste products of fat metabolism
– Presence in urine may indicate pending ketoacidosis
• Renal function:
– Urine protein without renal symptoms may indicate
microvascular changes
– Albumin at 30-3000 mg/hr indicates too much
protein in urine (microalbuminemia)
– Creatinine clearance tests
• Glucose:
– Blood glucose can be measured indirectly through
urine
 BLOOD TESTS
• Fasting blood glucose:
– Obtain blood thru venipuncture
– Fast for 8 hours
– Draw before Rx given; >126mg/dL X 2
• Oral glucose tolerance:
– Most sensitive test, but not routinely used
– Drinks beverage with 75 g of glucose; blood
samples are drawn at 30 min intervals for 2
hours. >200 mg/dL at 120 minutes
 BLOOD TESTS
• Glycosylated hemoglobin assays:
– Blood glucose attaches to hemoglobin
– Higher the glucose over time, > glycosyolated
hemoglobin
– Good indicator of average blood glucose levels
(HbA1c)
– Average glucose over last 120 days-life span of RBC’s
• Glycosylated serum proteins and albumim:
– Like hemoglobin, serum proteins and albumin become
satuated with glucose over time
– Turnover rate for proteins and albumin is 14 days,
therefore assesses glucose over shorter period of time
 DIABETES MANAGEMENT
MEALS
• MUST BE INDIVIDUALIZED
• NO SUCH THING AS “DIABETIC DIET”
• PORTION CONTROL IS THE KEY
• Goals include:
– Keep BS and HgbA1c normal
– Optimal lipid levels
– Optimal BP
– Ensure adequate calories
– Preventing complications
– Improve overall health
– Facilitate healthy eating habits
– Meet nutritional and psychological needs
– Provide self management education
– May help to facilitate moderate weight loss if at risk for
complications of obesity
 MEALS
• Day to day consistency in timing and amount
helps control blood glucose
• Protein, carbohydrates, and fats must be
consumed in appropriate amounts
– Protein- 15-20% of total daily calories in clients with
normal renal function (reduce to9 10% in renal
dysfunction)
– Fat- <10% saturated fats; up to 10% in
polyunsaturated fats
– Carbohydrates- emphasis in on total amount of
CHO, not source
 MEALS
• High fiber improve carbohydrate metabolism
and lower cholesterol (20-35 g of fiber per day)
• Increase fluid intake with fiber
• Nonnutritive sweeteners:
– Saccharin
– Aspartame
– Acesulfame K
– Sucralose
 MEALS
• Fat replacers:
– < 5 g of CHO per meal or < 20 calories
– Limit to 3 servings per day
– Excess calories from any source are
stored as adipose tissue and the storage
capacity is unlimited
 MEALS
• Alcohol:
– Moderate use if ok if diabetes is contolled; at risk for
hypoglycemia so ingest with meals
• Exchange system: no “one size fits all”
– Based on 3 food groups
– Individualized for each meal
• CHO counting
– Focus on total CHO amounts
– CHO controls blood glucose levels
– 1 unit of rapid-acting insulin for each 15 g of CHO
• Special considerations
– Type I- spread CHO over 3 meals; avoid gaining weight
– Type II- reduce calories eaten and increase calories expended;
3 meals with snacks
 MEDICATIONS
• All medications must be used along
with diet, exercise and stress
management
• Two types to control diabetes:
– Antidiabetic agents
– Insulin
 MEDICATIONS
• Oral therapy: prescribed after dietary
control has been proven insufficient or if
the client is highly symptomatic
• Classifications:
– Sulfonylureas
– Meglitnide analogs
– Biguanides
– Alpha-glucosidse inhibitors
– Thiazolidinedione antidiabetic agents
 MEDICATIONS: INSULIN
• Insulin therapy is needed for Type I and
many Type II diabetics
• Many types of insulin
• Dose varies but between 0.5-1 unit/kg/day
• Safety is issue for elderly patients, vision,
mobility, coordination, and memory
deficits
 INSULIN
• Types of insulin:
– Obtained for animal sources such as beef or pork
pancreas, combined, synthetic human and semi-
synthetic.
– There are differences in strength and onset of action
between human and animal insulins
– Human is more rapid acting, shorter peak action,
and shorter duration
– Human insulin is preferred during pregnancy or
with clients with allergies or resistance to animal
sources
 INSULIN
• Protocols:
– Single daily:
– Two-dose: 2/3 before breakfast; 1/3 in
evening
– Three-dose: breakfast, evening, bedtime
– Four-dose: before meals, bedtime
 INSULIN
• New technologies:
– Insulin pumps: Inject continuous basal doses of
insulin with increased doses at meals.
– Implanted insulin pumps: implanted into peritoneal
cavity where blood supply absorbs insulin.
– Needleless devices: ultrathin liquid is forced under
the skin with high pressure.
– Pen-type injectors: more precise smaller doses, easy
to carry and use.
– Inhaled insulin: under development; pellet that is
vaporized in an inhaler (like spiriva).
Photograph reproduced with permission of manufacturer.
 SUMMARY
• There is nothing inevitable about the
complications of diabetes.
• However, the evidence is overwhelming
that good control does count.
• Morbidity and mortality can be reduced.
 SUMMARY
• Insulin administration should mimic
nature
• Natures way is basal insulin 24 hrs. a
day.
• Insulin glargine or detemir can supply
the basal with one injection per day.
 SUMMARY
• Assessment tools include Self Monitoring
of Blood Glucose and HbA1C.
• Targets should be established for each of
these for each patients within the
national guidelines.
• When targets are not reached the help of
a specialist should be sought.
 THANK YOU

BIOCHEMISTRY FOR U, CHENNAI

http://biochemistryforu.googlepages.com/home