Transcript Pathophysiology

Pathophysiology
Glucose Homeostasis
&
Diabetes Mellitus
Glucose Homeostasis
Insulin secretion
 Counter-regulatory
Hormones

Insulin Secretion

Daily basilar level
– 40-50 U/day

Stimulated secretion
– BS 80-100mg/dl
– Secreted through
glucose metabolism
mediated
depolarization
– Membrane changes
promote Ca influx
and insulin secretion
http://www.montana.edu/wwwai/imsd/alcohol/Vanessa/vwpancreas.htm
Pancreas
Here is a normal
pancreatic islet of
langerhans surrounded
by normal exocrine
pancreatic acinar
tissue. The islets
contain alpha cells
secreting glucagon,
beta cells secreting
insulin, and delta cells
secreting somatostatin.
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ProInsulin
http://www.cebix.com/index.php/research/
Insulin Action
 Insulin
dependent glucose
transporters
 Storage of energy substrates
– fats
– amino acids
– glucose to glycogen
 Enhancement
of growth factor
activity
 Increase cellular uptake of K,
Phosphorus, and Mg
Counter Regulatory Hormones

Glucagon
– opposes insulin

Epinephrine
– mobilization of
glucose stores

Glucocorticoids
– decreases peripheral
utilization of glucose

Growth Hormone
– decreases glucose
uptake by tissues
Incretins
 Incretins
– group of gastrointestinal
hormones released in response to
eating
– Includes glucagon like peptide (GLP – 1)
which decreases need for glucagon
secretion
 Result
is increased insulin levels and
decreased glucagon levels
 Decrease gastric emptying and slow
the rate of absorption of nutrients.
Diabetes
 Group
of metabolic disorders
characterized by hyperglycemia
 Epidemiology
– 25.8 million people in US
– 8.3% of the population
– 1.9 million cases diagnosed each year
– Direct & Indirect costs exceed
$174 Billion
Diabetes
 Group
of metabolic disorders
characterized by hyperglycemia
 Classified by etiology
– Type 1 – Immune Mediated Diabetes
– Type 2 - Insulin Resistance with altered
insulin secretion
– Other Endocrinopathies
– Gestational diabetes
Categories for Increased Risk
for Diabetes
 Fasting
Plasma Glucose (FPG)
– 100mg/dl to 125mg/dl
– (5.6mmol/L to 6.9mmol/L
2
hour Post Prandial Glucose
– After 75 g oral glucose tolerance test
– 140mg/dl to 199mg/dl
– 7.8mmol/L to 11.0mmol/L
 Hgb
A1c 5.7 to 6.4%
Diagnostic Criteria
 Hgb
A1c > 6.5%
 FPG > 126 mg/dl (7.0mmol/L)
 2 Hour post prandial glucose >
200mg/dl (11.1 mmol/L)
 Symptoms of hyperglycemia in
conjunction with random glucose
>200 mg/dl
Diabetes
 Insulin
Secretion & Patterns of
Administration
– Link
Therapeutic Monitoring
 Evaluation
of Glycemic Control
 BP < 130/80
 Measurement of indices related to
end organ effects
– Neurologic assessment
– Visual screening
– BUN/Crt & Urine albumen levels
– Estimate GFR
– Lipid levels
Goals of Treatment
Hgb A1C
Less than 7%
Ideally less than 6%
without symptoms of
hypoglycemia
Preprandial
capillary plasma
glucose
90–130 mg/dl
(5.0–7.2 mmol/l)
Peak postprandial
capillary plasma
glucose
<180 mg/dl
(<10.0 mmol/l)
ADA (2012) Standards of Medical
Care in Diabetes - 2014
Correlation between A1C level and mean plasma glucose levels
Mean plasma glucose
A1C (%)
mg/dl
mmol/l
6
126
7.0
7
154
8.6
8
183
10.2
9
212
11.8
10
240
13.4
11
269
14.9
12
298
16.5
ADA (2012) Standards of Medical
Care in Diabetes - 2014
Type 1 Diabetes
 Molecular
mimicry
– Coxackie B virus
– Bovine Serum Albumin
 Genetic
links
– HLA antigens
 Insulinitis
Type 2 Diabetes
 Insulin
Resistance
 Reduction in Insulin secretion
 Genetic & Environmental factors
Type 2 Diabetes
 Genetic
& Environmental Issues
 Pathophysiology
– Abnormalities in adipoctes (accelerated
lipolysis)
– Neuroprotective mechanisms (excessive
appetite)
– Excessive hepatic glucose production
triggered by insulin resistance,
insulinopenia, and increased glucagon
secretion.
Acute Complications
 Hyperglycemia
– osmotic diuresis
 fluid
& electrolytes
– glucosuria
 Candida
– hyperphagia
 DKA
 HHNK
Hypoglycemia
 Counter
-regulatory hormone
secretion
 Enhanced Catecholamine secretion
 Neuroglycopenia
 Nocturnal Hypoglycemia
Catecholamine Secretion
Sweating
Shakiness
Anxiety
Palpitations
Weakness
Tremor
Hunger
Faintness
Tachycardia
Neuroglycopenia
Confusion
Irritability
Headaches
Abnormal behavior
Inappropriate affect
Coma
Weakness
Nocturnal Hypoglycemia
Morning Headache
Lassitude
Night sweats
Difficulty awakening
Nightmares
Loud Respirations
Chronic Complications
 Result
of pathophysiologic changes
 Ultimately lead to the development
of end organ effects
 End organ effects
– Renal
– Retinal
– Cardiovascular
– Neurologic
Chronic Complications
 Complications
– Link
 Microvascular
disease
 Macrovascular disease
 Neuropathy
Microvascular Disease
 Thickening
of basement membranes
 Advanced Glycosylated end products
 End organ effects
– Retinopathy
– Nephropathy
Microvascular Disease
 Retinopathy
– Microaneurysms, exudates, edema
– Neovascularization promotes retinal
detachment
 Nephropathy
– Alteration in glomerular function
– Proteinuria, hypertension, renal
insufficiency
– Glomerular sclersosi
Macrovascular Disease
 Acceleration
of atherosclerosis
 Increased VLDL
 Increased foam cell activity
 Imbalance in thrombotic and
fibrinolytic factors
Neuropathy

Vascular insufficiency - ischemia
 Neuronal
tissues -Altered metabolism
– non insulin dependent glucose
transporters
 Fructose
& Sorbitol
– Sorbitol excess
– altered cellular osmolality
– increased free radical formation
Autonomic Neuropathy
 Tachycardia
 Orthostatic
hypotension
 Incontinence
 Headaches