Current Diagnosis and Mechanisms of
Glucose Dysregulation
Dr. Josephine Carlos-Raboca
Chief, Section of Endocrinology, Diabetes & Metabolism
Makati Medical Center
Immediate Past President, PSEM
Outline
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Overview of glucose regulation
Stages of Dysglycemia (glucose dysregulation)
Current Diagnostic Criteria for dysglycemia
Mechanisms of Glucose Dysregulation
Summary
Glucose Metabolism
Tightly regulated to maintain adequate plasma levels
Major hormones
 insulin
 glucagon
 incretins
Major organs
 islet cells of pancreas
 insulin sensitive organs: liver, muscle, fat
 intestines
 Kidneys
Modulator
 Endocannabinoid System
Islet as an Organ:
Role of Pancreatic Islets in Normal
Glucose Homeostasis
Islet of Langerhans
~ 3,000 cells
200 µm 75% Beta cells
25% non-Beta cells
Micrograph: Lelio Orci, Geneva
Beta and Alpha Cells in the Pancreas of
Normal Individuals
Beta Cells
•
•
•
Alpha Cells
Comprise
about
50%
of the endocrine mass of
the pancreas1
Produce
insulin
and
amylin2
•
Insulin
released
in
response to elevated
blood glucose levels2
•
•
Comprise about 35% of
the endocrine mass of
the pancreas1
Produce glucagon2
Glucagon released in
response to low blood
glucose levels2 leading to
increase in glucose
1. Cabrera O et al. PNAS. 2006;103:2334–2339.
2. Cleaver O et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21–39.
Insulin Production


Primary regulators for insulin biosynthesis
 glucose
 glucagon
 incretins- GLP-1, GIP
Inhibits insulin biosynthesis
 catecholamine
 somatostatin
Glucagon

Main regulator- glucose
amino acids
 incretins
 Insulin
 fatty acids
 ketones
Insulin and Glucagon Regulate
Normal Glucose Homeostasis
Glucagon
(Alpha cell)
(–)
(–)
Pancreas
(+)
Insulin
(Beta cell)
(–)
(+)
(+)
Glucose uptake
Glucose output
Blood glucose
Liver
Muscle and
adipose tissue
Porte D Jr et al. Clin Invest Med. 1995;18:247–254.
Adapted from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
GUT and GUT Hormones


Na ATP channels – absorption of glucose
Incretins
Incretins Regulate Glucose Homeostasis
Through Effects on Islet-Cell Function
Ingestion of
food
 Insulin
in glucose-dependent way
from β cells
(GLP-1 and GIP)
GI tract
Release of
incretin gut
hormones
Pancreas
 INSULIN
β cells
α cells
Active
GLP-1 and GIP
Blood
Blood
glucose
control
control
↓ GLUCAGON
 Glucagon
Inactive
GLP-1 (9-36)
and GIP (3-42)
Increased
peripheral
glucose
uptake
in glucosedependent way
from α
cells (GLP-1)
Decreased
hepatic
glucose
output
Adapted from Brubaker PL, Drucker DJ. Endocrinology. 2004;145:2653-2659;Zander M et al. Lancet. 2002;359:824-830; Ahrén
B. Curr Diab Rep. 2003;3:365-372; Buse JB et al. In Larsen PR et al, eds.: Williams Textbook of Endocrinology. 10th ed.
Philadelphia, PA: Saunders; 2003:1427-1483.
The endocannabinoid system is a
modulatory system


Endocannabinoids:
 Synthesized
on
demand from lipid
precursors
in
postsynaptic cell
CB1 receptors:
 Play a key role in
energy balance and
lipid
and
glucose
metabolism
Di Marzo V et al, 2005; Di Marzo V et al, 1998;
Wilson R et al, 2002
Central and peripheral targets of
the endocannabinoid system
Brain
Peripheral tissues
Adipose
tissue
Hypothalamus:
^ hunger
Nucleus accumbens:
^ motivation to eat
Increased food intake
Increased fat storage
Liver
GI tract
Muscle
^ Insulin resistance
HDL-cholesterol
^ Triglycerides
Glucose uptake
Adiponectin
HDL: high-density lipoprotein
Bensaid M et al, 2003; Pagotto U et al, 2005;
Osei-Hyiaman D et al, 2005;
Di Marzo V et al, 2005; Liu YL et al, 2005
Regulation of glucose Homeostasis

Na dependent transporters in proximal tubules of
kidneys cotransport glucose with sodium
maintained by Na+/K+-ATPase ion pump
Glucose homeostasis

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Is a balance of glucose appearance and
disappearance
Glucose appearance:
endogenous glucose production (liver, muscle
and kidneys)
exogenous sources (GIT) affected by feeding
signals
Glucose disappearance
peripheral uptake from liver, muscle and fat
Current Diagnosis of
Prediabetes and Diabetes
Definition of Diabetes

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A metabolic dysregulation
Hallmark: hyperglycemia
Basic defects:
Islet cell dysfunction
 Insulin insensitivity
 Impaired action of insulin on target tissues
Definition of Diabetes

Chronic hyperglycaemia associated with longterm damage to:
 Eyes
 Kidneys
 Nerves
 Heart and blood vessels
Hyperglycemia
Stages
Type
Type 1 *
Type 2
Other Specific
Type *
Gestational
Diabetes **
Normal
Glucose
Regulation
Impaired Glucose Tolerance
or
Impaired Fasting Glucose
(Pre-Diabetes)
Diabetes Mellitus
Not insulin Insulin requiring Insulin requiring
requiring
for control
for survival
Diagnostic Criteria For DM
NORMOGLYCEMIA
IMPAIRED
FASTING
GLYCEMIA (IFG)
IMPAIRED
GLUCOSE
TOLERANCE (IGT)
DIABETES MELLITUS
FPG
2 hours PG (after 75 g
OGTT)
<<100mg/dL
110 mg/dL
(5.6mmol/l)
100mg/dl(5.6mmol)
110 and < 126 mg/dL
< 140mg/dL(7.8mmol/l)
---
and< 126 mg/dL(7.0)
---
 140mg/dl(7.8mmol/l)
and < 200
mg/dL(11.1mmol/l)
 126 mg/dL(7.0
mmol/l)
 200 mg/dL
(11.1mmol/l)
Symptoms of diabetes and casual plasma glucose
of  200 mg/dl(11.1mmol/l)
American
Diabetes Care
Association
ADA, Diabetes
2009 2003
Hba1c
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Integrated summary of circadian blood glucose in
the preceding 6-8 weeks
Not used as diagnostic test for diabetes
Lack of standardized analytical method and
therefore lack of a uniform non diabetic
reference level between laboratories
Insensitive in the low range
Normal aic cannot exclude diabetes or IGT
Issues on current diagnostic cut off
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3 studies on which FPG of 7.0 cutoff was based for
diagnosis of diabetes used direct ophthalmoscopic
examination and one retinal photograph
Diabetes Prevention Program showed substantial
prevalence of retinopathy below FPG of 7.0
Cardiovascular complications occur at lower glucose
levels
Definition and classification of diabetes and pre states
should be based on the level of subsequent risk of
cardiovascular complications class 1 level B ESC,EASD
2007
Relation between FPG and retinopathy

FPG
(Mean)

Number

(%) with
Retinopathy

Lancet 2008

BMES
5.3
364
(11.5)
AusDiab
6.5
210
(9.3)
MESA
5.9
959
(15.8)
Blue Mountains Eye Study (5-year incident retinopathy)
60
Any retinopathy
50
Percentage
40
30
20
10
0
< 4.6
4.7 - 5.4
5.5 - 6.2
6.3 - 7.0 7.1 - 7.8
7.9 - 8.6
8.7 - 9.4 9.5 - 10.2
> 10.3
Fasting plasma glucose (mmol/L)
Number with
any retinopathy
40
100
24
12
3
7
3
2
5
Total
545
996
241
56
21
15
9
5
15
Relation between baseline FPG and incident retinopathy, BMES
Recommendation

Current diagnostic criteria remain the best
tools for now.
Mechanisms of Glucose
Dysregulation and Development
of Type 2 Diabetes
Genetics
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39% of patients with type 2 diabetes have at least
one parent with the disease
Among monozyzgotic twin pairs with one
affected twin, approximately 90% of unaffected
twins eventually develop the disease
First degree relative of patients with type 2
diabetes frequently have impaired nonoxidative
glucose metabolism long before they develop
type 2 diabetes
Ethnic predilection
Environment
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Low birth weight
Gestational diabetes
Prematurity
Sedentary lifestyle
High fat diet
Physiologic & Molecular basis of Diabetes
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Physiologic
islet cell dysfunction
insulin resistance
Molecular
insulin receptor
Insulin signal transduction
Beta-Cell Function Is Abnormal
in Type 2 Diabetes

A range of functional abnormalities is present
 Abnormal oscillatory insulin release
 Increased proinsulin levels
 Abnormal insulin response
 Progressive loss of beta-cell functional mass
Adapted from Buchanan TA Clin Ther 2003;25(suppl B):B32–B46; Polonsky KS et al N Engl J Med 1988;318:1231–1239; Quddusi S et al
Diabetes Care 2003;26:791–798; Porte D Jr, Kahn SE Diabetes 2001;50(suppl 1):S160–S163.
First-Phase Insulin Response to IV Glucose
Is Lost in Type 2 Diabetes
120
Plasma insulin (µU/mL)
Plasma insulin (µU/mL)
120
Normal
100
80
60
40
20
Type 2 Diabetes
100
80
60
40
20
0
0
–30 0
30 60 90 120
Time (min)
n=9 normal; n=9 type 2 diabetes.
Adapted from Pfeifer MA et al. Am J Med. 1981;70:579–588.
–30 0
30 60 90 120
Time (min)
Fewer Pancreatic Islets in Type 2 Diabetes
Normal
Compensation
More islets
Larger islets
More beta cells/islet
Nondiabetic Obesity
Larger beta cells
Type 2 diabetes
Decompensation
Fewer islets
Fewer beta cells/islet
Amyloidosis
Adapted from Rhodes CJ. Science. 2005;307:380–384.
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Apoptosis (arbitrary units)
Increased Beta-Cell Apoptosis Occurs
in Type 2 Diabetes
2.5
*
2.0
1.5
1.0
0.5
0.0
Control
Type 2 diabetes
*p<0.05. Islet cell death was assessed by an ELISA method, which evaluates the cytoplasmic histone-associated DNA
fragments. After incubation absorbance of samples was read spectrophotometrically.
Data obtained from pancreatic islets isolated from 6 T2DM organ donors and 10 nondiabetic cadaveric organ donors.
Adapted from Marchetti P et al. J Clin Endocrinol Metab. 2004;89:5535–5541.
Amylin
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Amylin co-secreted with insulin
Low amylin levels in type 2 diabetes
cause or effect is unclear
Insulin
(µU/ml)
360
330
300
270
240
110
80
150
120
90
60
30
0
Glucagon
(µµg/ml)
Glucose
(mg/100 ml)
Insulin and Glucagon Response to a Large
Carbohydrate Meal in Type 2 Diabetes
140
130
120
110
100
90
Type 2 diabetes mellitus (n=12)*
Nondiabetic controls (n=11)
Meal
Depressed/delayed insulin response
Nonsuppressed glucagon
–60
0
60
Time (minutes)
*Insulin measured in five patients
Adapted from Müller WA et al N Engl J Med 1970;283:109–115.
120
180
240
Incretin Function in Type 2 Diabetes
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Secretion of GLP-1 impaired
Beta-cell sensitivity to GLP-1 decreased
Secretion of GIP normal (or slightly impaired)
Effect of GIP abolished or grossly impaired
Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723; Kjems LL et al. Diabetes. 2003;52:380–386;
Vilsbøll T et al. Diabetologia. 2002;45:1111–1119; Vilsbøll T et al. J Clin Endocrinol Metab. 2003;88:4897–4903.
37
The Pathophysiology of Type 2 Diabetes Includes
Islet Cell Dysfunction and Insulin Resistance
Glucagon
(Alpha cell)
Pancreas
Insulin
(Beta cell)
Glucose uptake
Glucose output
Hyperglycemia
Liver
Muscle and
adipose tissue
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Saunders, 2003:1427–1483; Buchanan TA. Clin
Ther. 2003;25(suppl B):B32–B46; Powers AC. In: Harrison’s Principles of Internal Medicine. 16th ed. McGraw-Hill, 2005:2152–2180;
Rhodes CJ. Science. 2005;307:380–384.
Adapted from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Insulin Resistance
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Genetics
Age
Weight
adipokines
Intra-abdominal adiposity is a
major contributor to insulin
resistance
IAA = high risk fat



Associated with
inflammatory markers
Dyslipidaemia
(C-reactive protein)
Free fatty
acids
Secretion of
adipokines
(↓ adiponectin)
Insulin
resistance
DM2
Increased
cardiometabolic
risk
Inflammation
IAA: intra-abdominal adiposity
Kershaw EE et al, 2004; Lee YH et al, 2005;
Boden G et al, 2002
endocannabinoid system
dysregulation
Weight-dependent
Weight Independent
Endocannabinoid system
Feeding
CB-1 blockade
Dyslipidaemia
Type 2 diabetes
Weight
Peripheral
insulin
resistance
Hepatic insulin
resistance
Hepatic
glucose
output
Adiponectin
FFA=free fatty acids
CETP=cholesterol
ester transfer protein
Low
HDL-C
CETP,
lipolysis
Lipolysis
TG-rich
VLDL-C
FFA
Visceral fat
Small,
dense
LDL-C
Portal
circulation
CB-1 blockade
Liver
CB-1 blockade
Modified from: Lam TKT, 2003;
Carr DB, 2004; Eckel R, 2005;
Pagotto U, 2005; Di Marzo V et al, 2005
Insulin Action


decrease in number of insulin receptors
any disruption in the transcription
transduction of insulin signaling pathway
or
Summary
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Glucose metabolism is tightly regulated to maintain
desirable glucose levels
Glucose dysregulation leads to progressive dysglycemia
from prediabetes to frank diabetes
The pathophysiology of type 2 diabetes is complex.
Involves multiple physiologic and molecular disturbances
influenced by multiple genes and environmental factors
This offers multiple target sites for therapy and explains
the complexity of treatment of DM2