Transcript Diabetes and Aging

Diabetes and Aging
MCB 135K
Ryan Klimczak
April 13th, 2007
Where is the pancreas?
Pancreatic endocrine functions
•
 cells: insulin (stores glucose)
•
 cells: glucagon (mobilizes glucose)
•
 cells: Somatostatin (regulatory,
inhibits endocrine pancreas)
•
PP cells: pancreatic polypeptide
(regulatory, inhibits exocrine pancreas)
•
The pancreas also has exocrine
functions, secreting enzymes needed
in digestion (pancreatic amylase,
trypsin, chymotrypsin, etc.)
Insulin vs. Glucagon
Insulin
• Anabolic (building) hormone
• Increases glucose transport to
muscles and adipose for use
• Stores excess glucose in liver
and muscles as glycogen
• Lowers blood glucose
• Inhibits gluconeogenesis
(endogenous glucose
production)
• Promotes growth overall
Glucagon
• Catabolic (breaking down)
hormone
• Breaks down glycogen to
increase blood glucose level
• Promotes gluconeogenesis
Table 14-2
Major actions of insulin
Glucose transport into
muscle & adipose cells
blood
glucose
intracellular
metabolic use
of glucose
glycogen synthesis
in liver and muscle
cells
gluconeogenesis
(in liver)
intracellular transport of
amino acids & lipids &
protein and triglyceride
synthesis
overall body
growth (general
effect)
Insulin’s function in detail
• Insulin is stimulated to be secreted by high blood glucose levels
(after a meal).
– Glucose binds to GLUT 2 receptor on B cell.
– Ultimately causes the exocytosis of insulin from B cells.
• Insulin binds to target cell receptors and this complex is taken into
the cell.
• Insulin now stimulates GLUT 4 to bring glucose into the cells.
• Glucose levels in the blood now decline
How does glucose cause insulin release?
How does insulin lower blood sugar?
Glucose from blood
vessel
Insulin primarily targets
muscle cells / adipocytes
Pancreas changes with aging
•
Atrophy
•
Increased incidence of tumor
•
Presence of amyloid material and lipofuscin granules (signs of abnormal cell
metabolism)
•
But these changes can’t account for the degree of metabolic change we see
in elderly individuals. There are also changes in sensitivity to insulin in the
body.
Glucose metabolism changes with aging
•
Studies show a slightly higher fasting blood glucose level in older individuals
•
Studies show elderly have inability to lower blood glucose as well as
younger people.
•
These 2 things can be called glucose intolerance
•
What causes glucose intolerance?
What is responsible for glucose
intolerance with aging?
• The pancreas: Insulin secretion may be depressed
• The peripheral tissue receptors may be resistant to insulin
• The liver may not be responding properly to insulin
It is widely believed that the glucose intolerance is due to insulin
resistance at the peripheral tissues.
Insulin resistance: an explanation for
glucose intolerance in elderly
• Insulin resistance: failure of insulin to stimulate glucose uptake by
peripheral tissue.
– No problem with insulin secretion, metabolism in the elderly
• Resistance due to
– receptor problem?
– Post-receptor pathway problem?
Due to defect in the signaling pathway once insulin has attached to
its receptor.
Why else do elderly have glucose
intolerance?
•
Loss of hepatic sensitivity to insulin and reduced glycogenesis
•
Increased glucagon levels (thus opposing insulin’s effects)
•
Changes in diet/exercise
•
Impaired glucose uptake in muscles and loss of muscle mass
•
Increase in adipose tissue (obesity) which may contribute to impaired
uptake in adipose tissue.
– Cell enlargement reduces the concentration of receptors on cell surface
– Overall decrease in absolute number of insulin receptors.
Defining diabetes type 2
•
Insulin resistance that meets criteria for
significantly impaired glucose tolerance,
as measured by fasting and glucose
tolerance tests.
– Glucose of 126 mg/dL or higher after
an overnight fast on more than one
occasion. (Fasting test)
– After 75 g oral glucose, diagnostic
values are 200 mg/dL or more 2
hours after the oral glucose.
(Tolerance test)
•
Insulin secretory capacity is partially
preserved (contrast to Diabetes type 1 in
which B cells are destroyed due to an
autoimmune response)
Prevalence/Risk factors
• 1999 study showed it affects 7% of US
population; 16-20% of adults over age 65.
• Risk factors:
– Age
– Reduced physical activity
– Obesity: adipocytes secrete factors
that modulate insulin activity in a
negative way (e.g. adipsin, TNF-alpha,
IL-6, MCP1, etc.)
– Ethnicity differences
• Need to screen high risk individuals
because symptoms show up late
Obesity trends and diabetes in the
United States 1990-2000
Impact:
-Nearly 21 million Americans are believed to be diabetic, according to the CDC,
and 41 million more are prediabetic.
-Diabetes is thought to shave 5 to 10 years off a life.
-Currently, it is the six leading cause of death in the United States, however the
condition is vastly underreported.
-Studies have found that only 35-40% of decedents have it listed anywhere on
the death certificate, and only 10-15% have it listed as the underlying cause of
death. The contributing role of diabetes in death is likely far higher.
-As many war veterans lost lower limbs last year to the disease as American
soldiers did to combat injuries in the entire Vietnam War.
Costs
-
Without complications, the average medical costs are $1600, but for more
severe conditions, the price quickly escalates: $30,000 for a heart attack or
amputation, $40,000 for a stroke, $37,000 for end-stage kidney disease
-
Nationwide, the disease's cost just for 2002 - from medical bills to disability
payments and lost workdays was estimated at $132 billion. (All cancers,
taken together, cost the country an estimated $171 billion a year) [American
Diabetes Association]
-
Increased incidence in future years may overwhelm healthcare system
Children and diabetes:
- Two (2) million adolescents (or 1 in 6
overweight adolescents) aged 12-19 have prediabetes.
- One in three children born in the United States
five years ago are expected to become diabetic
in their lifetimes, according to a projection by the
Centers for Disease Control and Prevention. For
Latinos: one in every two.
- The C.D.C. has projected that a child found to
have Type 2 diabetes at age 10 will see her life
shortened by 19 years.
Issues in treatment:
-Without symptoms or pain, most Type 2 diabetics find it hard to believe they are
truly sick until it is too late to avoid the complications that can overwhelm them.
- Acute care is more emphasized relative to chronic care because of profitability
for hospitals and the greater sense of urgency for patients and insurers
- Insurers will often refuse to cover a $150 for a diabetic to see a podiatrist or $75
to visit a nutritionist, while nearly all will cover the $30000 needed for an
amputation or $315 for a single dialysis session
Pathogenesis
• Caused by genetic and environmental influences
• Impaired insulin sensitivity at peripheral cells
• Impaired insulin secretion
• Increased liver production of glucose because liver not responsive to
insulin’s inhibitory effects on gluconeogenesis
• Often insulin secretion becomes impaired after a period of insulin
insensitivity, causing B cells to work too hard and thus fail
Consequences and
Pathophysiology of Type 2
Diabetes:
Microvascular changes
•Infections / Gangrene / Blindness /
Atherosclerosis
•Increased intra-luminal pressures,
weakened capillary walls in part due to
glycation- leading to vascular permeability,
microaneurysms, hemorrhages, and
ischemia
•This can result in the release of
vasoproliferative factors (e.g. VEGF),
leading to neovascularization and further
damage as in the case of proliferative
diabetic retinopathy
•For type 2 diabetics, 40% develop
retinopathy after 5 years, 84% by 15-19yrs
Consequences and
Pathophysiology of Type 2
Diabetes (con’t):
Macrovascular changes:
•Increased likelihood of heart disease and stroke
•Diabetes leads to hypercholesteremia, reduction in HDL
levels
•Microvascular changes compromise arterial wall
Neuropathy:
•Loss of gut motility, sensation changes in feet, etc.
•Glycation of nerves, comprised microvasculature, and
autoimmune responses may effect nerve structure,
leading to nerve damage, demyelination, and axonal
atrophy
•7% of Type 2 diabetes develop neuropathies after 1 yr
and 50% after 25yrs
Consequences and Pathophysiology of Type 2
Diabetes (con’t):
Diabetic nephropathy
•Kidney disease caused by angiopathy in the capillaries in the
kidney glomeruli causing increased extracellular matrix production,
endothelial damage
•Increased glomerular permeability leads to glomerular sclerosis
•Leads to fluid filtration deficits and ultimately renal failure
Theories of Complications
1.
High levels of glucose lead to formation of Advanced Glycosylation End
products (AGEs). They cross-link proteins and accelerate
atherosclerosis, kidney damage, artery wall damage
2.
Excess Glucose is metabolized through a different pathway, the sorbitol
pathway which more readily forms reactive oxidative species
3.
Excess glucose activates Protein Kinase C and alters other cellular
pathways, leading to deleterious changes in transcription/translation and
thus causing damage
4.
?
Treatment
Lifestyle modification
– Diet
– Weight loss
– Exercise
Pharmacologic
– Reduce insulin resistance
– Stimulate insulin secretion
– Give insulin
Transplantation
-Replace entire pancreas or some pancreatic islets