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Pathophysiology of Brain & Body
USSJJQ-20-3
Diabetes (part 1)
“Diabetes”
That which passes through…
• Diabetes
– Diabetes Insipidus (“…tasteless”)
– Diabetes Mellitus (“…honey”)
• Type 1 : Early Onset : IDDM
• Type 2 : Late Onset : NIDDM
• Atypical diabetes
• Metabolic Syndrome
Diabetes Insipidus (DI)
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Disorder arising from deficiency of anti-diuretic
hormone (ADH) or its action
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 copious amounts of dilute urine
Rare, 0.01% of hospitalisations in US
Central DI : failure of posterior pituitary gland to
secrete adequate ADH
Nephrogenic DI : renal tubules fail to respond to
circulating ADH
Inability of CT/CD to reabsorb water
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Lack of ADH-induced aquaporin 2 (‘water pores’)
Osmotic gradient between medullary interstitium and filtrate
still there, but cells of CD impermeable
 large volumes of dilute urine
 cellular and extracellular dehydration and hypernatremia
Water (and solute) balance
Net water
efflux
Net outward
water movement
Crenated
Normal
Hypertonic
Swollen
Isotonic
Lysed
Hypotonic
Increasing ion concentration in ECF
Bad
Bad
Less Water
More Water
Good
Posterior Pituitary
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Composed of nerve fibres
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These neurosecretory cells synthesize Oxytocin
& Vasopressin (ADH)
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cell bodies in hypothalamicparaventricular &
supraoptic nuclei
pass down nerve fibres & stored in/released from
the posterior pituitary
both nine-AA peptides
ADH release stimulated by...
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Plasma osmolarity >280 mOsm/L
Fall in plasma volume
Emotional factors/stress
Sleep
Effect of ADH on nephron water permeability
No ADH
Water Permeability
100,000
+ ADH
10,000
1,000
100
10
PCT
tdL TAL DCT CCD IMCD
Nephron Segment
Osmotic Gradients and Urine Conc
Always ~100!
regardless of
hydration
Effects/Causes/Treatment
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Effects
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Causes (central)
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polyuria, polydipsia, nocturia/enuresis, hypernatraemic dehydration
Idiopathic (30%)
Tumours (30%)
Infection, trauma, thyroiditis, leukaemia, genetic (AD, X-link)
Treatment (central)
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Desmopressin (DDAVP)
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Causes (nephrogenic)
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Synthetic analogue
Longer half-life
More potent, more specific for renal effects
familial: X-linked recessive
Renal disease (chronic renal failure, polycystic)
Treatment (nephrogenic)
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Adequate fluid intake, low sodium diet, diuretics
Diabetes Mellitus (DM)
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Group of metabolic diseases characterised by
hyperglycemia
Results from defective insulin secretion and/or
action
Chronic hyperglycemia 
long-term damage/dysfunction/failure
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Main players…
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eyes, kidneys, nerves, heart, and blood vessels
glucose
glucose transporter
insulin
insulin receptor
Increasing prevalence/burden  ‘epidemic’
diasoce1.ppt
13
Diabetes: Complications
Macrovascular
Stroke
Microvascular
Diabetic eye disease
(retinopathy and
cataracts)
Heart disease and
hypertension
Renal disease
Peripheral
vascular disease
Erectile
Dysfunction
Peripheral
Neuropathy
Foot problems
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
Diabetes: Burden
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Leading cause of blindness (12.5% of cases)
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Leading cause of End-Stage Renal Disease, ESRD
(42% of cases)
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50% of all non-traumatic amputations
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2.5x increase risk of stroke
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2-4x increase in cardiovascular mortality
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DM ‘responsible’ for 25% of cardiac surgery
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Mortality in DM: 70% due to Cardiovascular Disease
Haffner et al, NEJM, 339(4):229-34, 1998.
Diabetes: A Very Brief History
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2nd Cent AD: “diarrhoea of the urine”... “the thirsty
disease” Galen. “Diabetes is a wonderful affection, not
very frequent among men, being a melting down of the
flesh and limbs into urine” Aretaeus the Cappadocian
1850s autopsies suggest link with pancreas (patients
with damaged pancreases almost always had DM)
1869: Paul Langerhans discovered existence of
pancreatic acinar cells (pancreatic juice) and islets
floating among the acini with an unknown function
1889: Minkowski & Von Mering depancreatized a dog
 polyuria as in diabetes. Ligating ducts did not 
DM (so not pancreatic juice)
1916: Paulescu normalized a diabetic dog with
aqueous pancreatic extract
1955: Sanger’s group sequences bovine insulin
Islet of Langerhans with acinar cells
Insulin and Glucose Homeostasis
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Part of a larger picture…
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Organs…
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Glucose, Lipoprotein, Protein, Ketone metabolism
Endocrine pancreas
Adipose tissue, Liver, Gut, Skeletal muscle, Kidneys
Hormones…
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Pancreatic hormones
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Insulin (β-cell)
Glucagon (α-cell)
Amylin (β -cell)
Intestinal Hormones (Incretins)
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GLP-1 (L-cells) - Glucagon-like Peptide
GIP (K-cells) - Glucose-dependent Insulin-releasing Peptide
Insulin and Glucose Homeostasis
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Terms…
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Glycogenolysis
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Gluconeogenesis
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Ability of insulin to lower circulating glucose concentrations
Insulin Resistance
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Production of ketone bodies
‘emergency’ fuel for heart/skeletal muscle
Insulin Sensitivity
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Production of glucose from non-carbohydrates or proteins
Ketogenesis
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Catabolism of glycogen
Condition of low insulin sensitivity
Honeymooning
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The ability of the failing β -cells to become hyper-productive and
compensate for failing insulin response
Simple Homeostasis
Homeostasis: Norm vs DM (Type 1?)
Glycosuria/Diuresis in DM
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Renal Filtered Load = [Plasma Gluc] x GFR
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Reabsorption is via facilitated transport
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Finite number of sites
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therefore Transport Maximum, TMax
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Hyperglycaemia  increased Filtered Load
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When nears/exceeds TMax
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 glucose remains in tubule
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Osmotic effects of glucose ‘trap’ water in tubule
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Get glucose in urine plus osmotic diuresis
DM and Glycosuria
Glucose Metabolism
Major Metabolic
Effects of Insulin
Stimulates
glucose
uptake into muscle
and adipose cells
Inhibits
hepatic
glucose production
Consequences of
Insulin Deficiency
Hyperglycemia
osmotic diuresis and
dehydration
Insulin Overview
Hepatic glucose output
_
INSULIN
Blood [Glucose]
diet
+
Peripheral
Tissue
Uptake
Lipoprotein Metabolism
Major Metabolic
Effects of Insulin
Consequences of
Insulin Deficiency
Inhibits
Elevated
breakdown
of triglycerides
(lipolysis) in adipose
tissue
FFA levels
Ketone Metabolism
Major Metabolic
Effects of Insulin
Inhibits
ketogenesis
(Ketogenesis: is the
process by which
ketone bodies are
produced as a result of
fatty acid breakdown)
Consequences of
Insulin Deficiency
Diabetic
Ketoacidosis (DKA)
DKA: Pathophysiology
Glucose
Ketoacids
fat cell
TG
Insulin -
HSL
FFA
Insulin +
PFK
Liver Cell
Pyruvate
Acetyl-CoA
Kreb’s
+
Fatty
Acyl-CoA
Glucagon
Insulin
+
VLDL (TG)
DKA: Pathophysiology
Glucose
Ketoacids
fat cell
TG
Insulin -
HSL
FFA
Insulin
PFK
Liver Cell
Pyruvate
Acetyl-CoA
Kreb’s
+
Fatty
Acyl-CoA
Glucagon
Insulin
+
VLDL (TG)
Protein Metabolism
Major Metabolic
Effects of Insulin
Stimulates
amino
acid uptake and
protein synthesis
Inhibits protein
degradation
Regulates gene
transcription
Consequences of
Insulin Deficiency
Muscle
wasting
Overall
catabolic rather
than anabolic
effects
Insulin Secretion: Constitutive/Regulated
• Constitutive secretion maintains sensitivity of islets to
glucose?
Insulin Secretion: Regulation by Glucose
Insulin Action: Glucose Transport
Insulin causes receptor autophosphorylation
Insulin Action: Glucose Transport
Activated insulin receptor phosphorylates IRS-1
Insulin Action: Glucose Transport
Phosphorylated IRS-1 activates PI-3 kinase
Insulin Action: Glucose Transport
PI-3 kinase converts PIP2 => PIP3 (activates PDK1)
Insulin Action: Glucose Transport
PDK1 activates protein kinase B (PKB)
Insulin Action: Glucose Transport
PKB stimulates GLUT-4 translocation
Bigger Picture: More than Insulin…
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Glucagon – glycogen breakdown, gluconeogenesis
Adrenaline, noradrenaline – glycogen breakdown and
gluconeogenesis in muscles, lactate  glucose in liver
Growth hormone (anabolic hormone), lipolysis,
protesynthesis
Glucocorticoids – gluconeogenesis, block of
proteosynthesis
Thyroid hormones and oestrogens
Amylin – Co-secreted with insulin; anorectic (acts on
brain  ‘sated’ feeling)
GLP-1 - “Incretin” hormone secreted by GI cells in
response to a meal; +ve insulin secretion/sensitivity