b cell mass and regeneration
Susan Bonner-Weir
Translational Working Group
on b cell and Islet cell Dysfunction
January 10, 2009
Diabetes results if there is an
inadequate functional b cell mass.
This inadequacy can be due to:
• destruction (type 1)
• functional defect (MODY)
• inability to compensate for
demand/ insulin resistance (type 2).
In humans b cell mass increases with obesity
In diabetes, b cell mass is reduced to 50%
b Cell Mass (% of Lean Control)
150
125
100
75
50
25
6
7
4
8
0
Obese Obese
Lean Lean
Diabetic Diabetic
Kloppel G, et al. Surv Synth Pathol Res. 1985;4(2):110-25.
Relative b Cell Volume (%)
Increased b cell volume with obesity in humans
In diabetes, b cell mass Is reduced about 50%
Mayo series
BMI
Nondiabetic
Lean 22.5±0.5
Obese 36.3±1.3
3
2
1
16
30
19
16
41
0
Lean Obese Obese
Nondiabetic
IGT
Butler AE, et al. Diabetes. 2003;52:102-10.
Lean Obese
Diabetic
Can a given b-cell mass put out much more insulin?
Absolutely!
With obesity, b-cell mass is only 30- 50% increased,
but insulin secretory output increased 100%.
(24 hr output of insulin: 468 versus 235 nmol)
Camastra S, et al. Diabetes 54:2382, 2005
So functional as well as physical increases of b
cell mass lead to compensation/adaptation.
In vivo measures of b cell function (AIR arginine, AIR glucose
and glucose potentiation of AIR arginine) approach 0 when
still 40-50% of the b cell mass remains (baboons).
Non diabetic
Insulin requiring diabetic
Non-insulin requiring diabetic
McCulloch et al Diabetes 1991
There is a slow continual turnover of b cells
with compensation to increased/decreased
demand.
b cell death
b cell birth
Replication
(from b cell)
b cell mass
(Number x volume)
Neogenesis
(from progenitor
or stem cell)
b cell volume
Hypertrophy vs atrophy
Apoptosis
Human islets are 70% b cells and are 1-2% of pancreas
Glucagon
64 yr female, BMI:20.8
In type 2 diabetes islets have decreased b cells, due
to amyloid formation and loss of b cells
Large islets with low % b cells
Amyloid deposits with loss of b cells
Glucagon
Bonner-Weir S & O’Brien T Diabetes 2008
Glucagon
insulin
KH Yoon et al, JCEM 2003
b cell mass (total volume) is dynamic
b cell death
b cell birth
Replication
(from b cell)
b cell mass
(Number x volume)
Neogenesis
(from progenitor
or stem cell)
b cell volume
Hypertrophy vs atrophy
Apoptosis
b cell mass is dynamic and is regulated to
maintain glucose homeostasis.
Marked increases in b cell mass in rodents:
•
•
•
•
•
•
In models of insulin resistance
After glucose infusions
In transplanted islets with induced hyperglycemia
After removal of transplantable insulinoma
After partial pancreatectomy (regeneration)
During pregnancy
Adult human b cells have very low replication
rate but can be stimulated to replicate
Insulin
Ki67
Dapi
45 yr old donor
islets transplanted into normoglycemic NODscid mouse
Hormone positive cells budding from ducts = neogenesis
Adult human pancreas
insulin immunostaining
So, why is the b cell mass in people with type 2 DM
only 50% of that of non diabetics with similar BMI?
Why is it lower already in IGT?
1. Increased apoptosis
2. Inadequate compensation (replication and/or
neogenesis) for increasing insulin resistance
3. Contributions from both 1 and 2 - a minor
imbalance will result in a gradual reduction in mass
and then loss of function of remaining b cells.
Speculation: b Cell Mass During Progression of DM
150
125
100
Normal
%
75
50
25
Type 1 DM
T2DM: Model #1
0
30
Time (years)
60
• While most of what we know about b cell mass
comes from rodents, human b cells have same
processes of growth and death.
• Actual b cell mass may not be same as functional
mass due to effects of hyperglycemia.
• Decreased b cell mass already at IFG/IGT suggests
that the time for therapies to preserve or replenish is
early.