The Common Denominator: The Role of Diabetes

in Cardiovascular and Kidney Diseases

Part I: Energy Homeostasis - The Key to Understanding Diabetes

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Table of Contents
Introduction to Diabetes………………………………………………………………………….……………….....3
Energy Homeostasis.…………………………………….………………………...….……………………………….5
The Importance of the Pancreas……………………………………………………..….……….……………….6
What Is Diabetes?
Type 1 Diabetes………………………………………………………………..………….………...................8
Type 2 Diabetes.………………………………………………………..………………….………..................9
Why Diabetes and Obesity Research Isn’t a Luxury, It’s a Necessity……….………….…..…..10
Diabetes and Obesity Biomarkers Making a Difference……………..……..…….........................11
Proinsulin……………………………………………………………………………………………………….....12
C-peptide.………………………………………………………………………………………………………....14
Adiponectin.………………………………………………………………………………………………………16
Glucagon Like Peptide-1……………………………………………………………………………………..18
Glucagon.……………………………………………………………………………………………………….…20
Part I Summary…………………………………………………………………………………………………….……22
References…………………………………………………………………………………………………………….…..23
About ALPCO……………………………………………………………………………………………………………25
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Diabetes
The prevalence of diabetes and obesity has been on the rise for several decades. According to the American Diabetes
Association, approximately 30 million adults and children are living with diabetes in the US and another 84.1 million
Americans have prediabetes1. Furthermore, the healthcare burden of diabetes in the US has also risen from an
estimated $174 billion in 2007 to $245 billion in 20132. By 2030, 552 million people worldwide are expected to
have diabetes3.

Healthcare Burden of Diabetes

250

200

150
Billions

100

50

0
2007 2013
$174 $245

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The Role of Diabetes in Cardiovascular and Kidney Diseases
Research has demonstrated that diabetes can very well cause problems in other parts of the body including the cardiovascular
system and the kidneys. 65% of diabetics will pass away from cardiovascular disease4 and 33% will develop diabetic kidney
disease3. Biomarkers are becoming more important in diabetes research to find ways to detect these complications sooner,
leading to faster and more appropriate treatments.

The Common Denominator, is a three part eBook series that reviews diabetes, cardiovascular and kidney complications
associated with diabetes, and biomarkers that have become important in researching these areas.

Part I: Energy Homeostasis reviews the principles behind the development of diabetes and emerging biomarkers being used
in diabetes research.

65% of diabetics will die from 33% of diabetics will develop

cardiovascular disease. kidney disease.

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Introduction to Energy Homeostasis
Energy homeostasis is a well-
regulated process that depends
on the coordination between
feeding behavior and energy
expenditure. The control of
energy homeostasis in humans
has received much attention in
recent years due to alterations
caused by the onset of conditions
such as obesity and diabetes.

A variety of organs tightly control

energy homeostasis including
the:

• Pancreas
• Stomach
• Intestine
• Brain
• Liver

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The Importance of the Pancreas
The pancreas is one of the most
important organs involved in
maintaining energy homeostasis
because it is responsible for the
secretion of insulin and glucagon.

Insulin and glucagon are two counter

regulatory hormones that control the
systemic concentration of glucose,
a metabolic intermediate used by cells
as the primary source of energy.

Many different types of cells in

the pancreas contribute to energy
homeostasis by producing different
proteins and hormones.

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The Pancreatic Islets of Langerhans
The pancreas releases insulin
and glucagon directly based on Increase in Decrease in
the concentration of glucose in
the blood. circulating circulating
glucose glucose
Not only is insulin secretion
regulated in this direct fashion,
it is also controlled by the Food intake
incretins GIP and GLP-1, a
group of gastrointestinal α-cell β-cell Satiety
hormones that cause an glucagon insulin regulates
increase in the amount of islet function
insulin released from β-cells
after eating, even before
blood glucose levels become
elevated.
+ + +
If glucose homeostasis is
thrown off balance, a diabetic
state develops.
Liver Adipose Muscle cells
Glucagon Fat ↔ glucose Glucose transport
production: GLUT4-lipogenesis GLUT4-glycogenesis
gluconeogenesis β oxidation
glycogenesis

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What Is Diabetes?
Type 1 Diabetes
(T1D, juvenile diabetes)

Type 1 diabetes is an auto-

immune disease that results in
the destruction of β-cells in the
pancreas. With the destruction
of β-cells, the body cannot
produce enough insulin to
maintain energy homeostasis
and the concentration of glucose
in the body increases. Cells are
unable to access glucose to use
as energy12.

Onset of type 1 diabetes

typically occurs in children
and young adults, but the
causes behind this develop-
ment are not yet fully known13.

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What Is Diabetes?
Type 2 Diabetes
(T2D, adult onset
diabetes, noninsulin
dependent diabetes)

Type 2 diabetes occurs

when the body has built
up a resistance to insulin,
causing glucose levels
in the body to increase
by preventing glucose
uptake into cells12.

Onset of type 2 diabetes

usually occurs in adults,
but children can also
develop type 2 diabetes14.
The direct causes of type 2
diabetes have not been
fully discovered, but
there are many risk factors
in the development of
the disease including
NGT = Normal glucose tolerance
obesity15. IGT = Impaired glucose tolerance

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Why Diabetes and Obesity Research Isn’t a Luxury,
It’s a Necessity
Research in diabetes and obesity is
more important than ever.

Obesity in the US continues to increase

at alarming rates:
• 31.5% of the population was
obese in 2001, compared to
35.5% in 201216
• Rates of childhood obesity tripled
from 1980 to 201016

Diabetes is closely related to obesity,

so the increase in obesity has had an
impact on the number of people with
diabetes:
• 29.1 million children and adults in
the US are living with diabetes17
• The percentage of people with
diabetes has nearly doubled since
199717

In addition, improvements in testing

and screening have helped doctors to
identify more cases of diabetes.

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Diabetes and Obesity Biomarkers Making a Difference
Insulin
(INS)

Proinsulin C-peptide
(PI, PIN) (CP)

Adiponectin Glucagon like peptide-1

(ADP) (GLP-1)

Glucagon

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Proinsulin (PI, PIN) C β-cell

Intact PI
A
Proinsulin is a precursor molecule of
insulin (INS) and C-peptide (CP) that B
is synthesized by pancreatic ß-cells Proinsulin
within the Islets of Langerhans19,20,21.

Measuring proinsulin is a better

window into β-cell function than
traditional type 2 diabetes markers Split-32,33-Proinsulin Split-65,66-Proinsulin

Partially Processed PI
(i.e. HbA1c, fasting insulin) and is
CPE/H CPE/H

Total PI
an early marker of type 2 diabetes
progression22,23. Proinsulin has low
bioactivity and 3x longer half life than
insulin. The increase in concentration
of proinsulin and in the proinsulin/
insulin ratio is present in diabetic Des-31,32-Proinsulin Des-64,65-Proinsulin
states22. PC2 PC1/3

Research areas:
• Type 2 diabetes progression
• Cardiovascular disease
• Research in animal models
• Pre-clinical testing of drug Split-65,66- Des-31,32- Split-32-33- Des-64,65-
candidates for therapeutics Proinsulin Proinsulin

A B

PI  INS + CP
C

Insulin C-peptide

Adapted from 19,20,21 12

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Researching Diabetes and Obesity with Proinsulin:
As insulin resistance (IR)
progresses, β-cells try to
compensate to elevated
insulin (INS) demand in the
fat, muscle and liver by
increasing insulin secretion.
This results in elevated
circulating insulin con- Type 2 diabetes progression model –
centration known as insulin resistance, secretion and proinsulin
hyperproinsulinemia24,25.

Continually high demand

of insulin can lead to a
decline in β-cell function,
health, and mass. The
deterioration of β-cells is
related to the progression
of type 2 diabetes23,24,25.
Insulin

Hyperproinsulinemia is an
early defect observed in
human type 2 diabetes
pathogenesis which makes
proinsulin an early pre-
diabetic marker24,25:
Time
• Healthy
[PI]/[INS]=~5%26;
• In β-cell stress Adapted from 19,24,24,27

[PI]/[INS]=~60%26!
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C-peptide
C-peptide is the amino acid sequence that links the A and B chains of the proinsulin molecule together. It is secreted in 1:1
molar amounts with insulin, but is only cleared by the kidneys, resulting in a longer half life of approximately 30 minutes.
Measuring C-peptide is often more useful to quantify β-cell function and mass without having to account for variances in
insulin clearance. C-peptide secretion shows the true output of β-cell response to glucose.30,31,32

Additionally, evidence supports that C-peptide binds peripheral neuronal cells and can therefore aid in the study of diabetic
neuropathy33,34.

Research areas:
• β-cell function
• Diabetic kidney disease
• Cardiovascular disease

Adapted from 19
14

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Researching Diabetes and Obesity with Proinsulin
and C-peptide
Together, proinsulin and C-peptide are important biomarkers for assessing β-cell function, cell mass, and health.12,35,36

β-cell Function/Mass

Insulin Secretion Insulin Sensitivity Insulin Resistance

PI  INS + CP
15
Adapted from 12,35,36

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Adiponectin (ADP) Cell proliferation

Pancreas
ADP is a 244 amino acid protein
exclusively secreted from adipose Insulin secretion
(fat) cells and is very abundant
in plasma (~5-10 μg/mL)15,37.
This “adipocytokine” is a strong
indicator of insulin sensitivity Increases glucose
and resistance38. ADP has been uptake
shown to affect multiple areas Adipose tissue
of the body in different ways39.
Regulates fat lipid
There are several isoforms of metabolism
ADP in circulation, but usually
Adiponectin
High Molecular Weight (HMW),
Total ADP, and the ratio of HMW/ Protects against
Cardio
Total ADP are measured40,41. inflammation

Research areas:
• Metabolic syndrome May cause
Kidney
• Obesity kidney damage
• Type 2 diabetes
• Coronary artery disease
• Pharmaceutical drug Activates glucose
development target transport
Liver
Inhibits
gluconeogenesis

Adapted from 39,42,43 16

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Researching Diabetes and Obesity with ADP
HMW ADP and the ratio of
HMW/Total ADP are more ADP: ISOFORMS & TOTAL
relevant to type 2 diabetes, ADP
obesity, and coronary artery
disease.46,47,48 Trimer (LMW) ADP: The basic circulating form that is formed by 3 monomers

HMW ADP
( ) ( + =
)
A

+ + = l
b A

• More active with longer

l
b
Monomer Monomer Monomer Trimer Albumin
half life42
• Exhibits the highest AMP
kinase phosphorylation38
• Major insulin-sensitizing Hexamer (MMW) ADP: Trimeric ADP is further assembled into Hexamer ADP
effects of the multiple
bioactive forms47
• More useful than Total ( Trimer
+ = )
ADP for predicting IR and Trimer

the development of
metabolic syndrome46,47
HMW ADP: Hexamer further assembles into multiple HMW forms (12, 18, 24, 30mer etc.)
Total ADP

( + =
) ( )
• Elevated concentration
S- + =
is considered good, S- S-
but higher HMW ADP Hexamer Hexamer S S Hexamer S
HMW-
concentration is con- ADP (12)
sidered even better46 HMW ADP HMW ADP
• ↓[ADP] = ↑Metabolic (12=Dodecamer) (18=HexaDodecamer)
syndrome, obesity and
type 2 diabetes43
• ↓[ADP] = ↑Coronary Adapted from 43,47
artery disease, coronary
heart disease37 17

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Glucagon Like Peptide-1 (GLP-1)
GLP-1 is produced in intestinal L-cells in response to food Brain
and is well conserved across species. GLP-1 is derived from
the cleavage of proglucagon to generate a 1-37 amino acid
Neuroprotection
peptide. Fasting reduces circulating levels of GLP-1. GLP-1 Appetite
has many physiological effects on the body49.

Stomach
Heart
Gastric
Cardioprotection emptying
Cardiac output

GLP-1
Insulin secretion
Skeletal muscles Glycogen synthesis
Insulin Glucagon secretion
Biosynthesis
β-cell proliferation GI tract
β-cell apoptosis Insulin sensitivity
Pancreas

Brown adipose
Liver tissue (BAT)
thermogenesis
Glucose Adipose tissue
production
Adapted from 49,50,51,52,

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Researching Diabetes and Obesity with GLP-1
Diabetes and obesity scientists have been using two main
GLP-1 research approaches: DPP-4 inhibition and GLP-1
analogs. DPP-4 can inactivate GLP-153,54:

By inhibiting DPP-4, scientists hope that GLP-1 can

continue to influence insulin secretion and restore
balance to energy homeostasis53,54.

The goal of developing GLP-1 analogs is to engineer a

better GLP-1 molecule that has a longer half life, thus
providing longer influences over insulin secretion53,54.

55

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Glucagon
Glucagon is produced by
α-cells in the pancreas in
response to low circulating
glucose54.

The hormone acts on

the liver to promote
gluconeogenesis, turning
glycogen into glucose56.

Fasting state glucagon

levels are high and fed
state levels are low57.

Research areas:
• Metabolic syndrome
• Obesity
• Type 2 diabetes
• Coronary artery
disease
• Pharmaceutical drug
development target

Adapted from 50

20

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Researching Diabetes and Increases heart rate
and lipid oxidation

Obesity with Glucagon Heart

Decreases
cardiomyocyte
survival

Glucagon is essential for the maintenance of

normal blood glucose in diabetes57. Increases lipolysis
Adipose tissue and thermogenesis

It plays a role in hepatic fatty acid oxidation

and ketogenesis57.
GI tract Decreases motility
Glucagon activates brown adipose tissue (BAT)
thus directly regulating it58.
Increases glomerular
Increase in energy expenditure and reduction in Glucagon Kidney filtration and water
reabsorption
food intake are also modulated by glucagon57,59.

Increases satiety
Research areas:
• Metabolic syndrome Brain
• Obesity
Decreases hepatic
• Type 2 diabetes glucose output
• Coronary artery disease
• Pharmaceutical drug development target
Increases hepatic
glucose output, lipid
oxidation, and
hepatocyte survival
Liver
Decreases lipid
synthesis

Adapted from 57,58,59,60

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Summary
Understanding energy homeostasis is the key to understanding diabetes. The pancreas has the
important role of maintaining this energy balance in the body. Diabetes develops when there is a
disruption of energy homeostasis and the form of the disease depends on how the imbalance occurs.
Despite the strides being made in diabetes and obesity research, further investigation of biomarkers
is needed to help improve the lives of diabetics.
For product information on the biomarkers presented in Part I, click here. The Common Denominator
will continue with Part II: Connecting Diabetes and Cardiovascular Disease which will examine the
effects diabetes has on the cardiovascular system, as well as biomarkers important to researching
both diseases.

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Planning a Research Project?
Please contact us to share how your research is contributing to the battle against
diabetes and obesity.

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About ALPCO
American Laboratory Products Company (ALPCO) was founded in 1991 as an importer and distributor of immunoassay-based products for the
North American life science markets. Our origin began through an exclusive partnership with one European manufacturer and has since grown into
a premier channel representing over 60 collaborating partners from around the globe. In 2008, we expanded our capabilities with the launch of
our organically developed product line focused in the area of diabetes and obesity research while also remaining true to our roots by continuing to
provide “Immunoassays Beyond the Ordinary.”

As the research and diagnostic endeavors of our customers continue to evolve, so does ALPCO’s commitment to providing high quality products and
superior customer support. Over the years we’ve expanded our offering into applications for HPLC, LC-MS/MS, purified antibodies, recombinant
proteins, flow cytometry reagents and recently launched our new STELLUX® line of chemiluminescent based detection systems in 2013. Additionally,
our promise to provide optimal support continues to progress through a growing network of valuable online resources, collaborative relationships,
and customized technical solutions. While our vision has adapted to serve a broader segment of life science research and healthcare professionals,
our mission to deliver “Scientific Solutions for Life” remains the same.

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(800) 592-5726 www.alpco.com