β cell mass and regeneration

Susan Bonner-Weir

Translational Working Group

on β cell and Islet cell Dysfunction
January 10, 2009
Diabetes results if there is an
inadequate functional β 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 β cell mass increases with obesity
In diabetes, β cell mass is reduced to 50%
150
β Cell Mass (% of Lean Control)
125

100

75 6
7
50
4
25 8

0
Lean Lean Obese Obese
Diabetic Diabetic

Kloppel G, et al. Surv Synth Pathol Res. 1985;4(2):110-25.

 Increased β cell volume with obesity in humans In
diabetes, β cell mass Is reduced about 50%
Relative β Cell Volume (%)
Mayo series
BMI
3
Nondiabetic
Lean 22.5±0.5
2 Obese 36.3±1.3

1
16 30 19 16 41

0
Lean Obese Obese Lean Obese
Nondiabetic IGT Diabetic
Butler AE, et al. Diabetes. 2003;52:102-10.
Can a given β -cell mass put out much more insulin?
Absolutely!
With obesity, β -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 β

cell mass lead to compensation/adaptation.
In vivo measures of β cell function (AIR arginine , AIR glucose and
glucose potentiation of AIR arginine ) approach 0 when still 40-
50% of the β 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 β cells with
compensation to increased/decreased demand.

β cell birth β cell death

Replication
(from β cell)
β cell mass Apoptosis
(Number x volume)

Neogenesis
(from progenitor
or stem cell)
β cell volume
Hypertrophy vs atrophy
Human islets are 70% β cells and are 1-2% of pancreas

Glucagon 64 yr female, BMI:20.8

 In type 2 diabetes islets have decreased β cells,
due to amyloid formation and loss of β cells
Large islets with low % β
cells
Amyloid deposits with loss of β cells

Glucagon
Bonner-Weir S & O’Brien T Diabetes 2008 Glucagon insulin
KH Yoon et al, JCEM 2003
 β cell mass (total volume) is dynamic

β cell birth β cell death

Replication
(from β cell)
β cell mass Apoptosis
(Number x volume)

Neogenesis
(from progenitor
or stem cell)
β cell volume
Hypertrophy vs atrophy
β cell mass is dynamic and is regulated to
maintain glucose homeostasis.

Marked increases in β 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 β 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 β 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 β cells.
Speculation: β Cell Mass During Progression of DM
150

125

100
Normal
%
75 T2DM: Model #2
?Low birth weight
50

Type 1 DM T2DM: Model #1

25

0
30 Time (years) 60
• While most of what we know about β cell mass comes
from rodents, human β cells have same processes of
growth and death.

• Actual βcell mass may not be same as functional

mass due to effects of hyperglycemia.

• Decreased β cell mass already at IFG/IGT suggests

that the time for therapies to preserve or replenish is
early.