PREDICTION OF DIABETES MELLITUS TYPE II

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PREDICTION OF DIABETES MELLITUS TYPE II -NEW
DIAGNOSTIC PERSPECTIVES-
Adlija Jevric-Causevic Faculty of Pharmacy,
University of Sarajevo
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I would like to thank to the members of the BCLF
organizing commitee for giving me the opportunity
to give this presentation. I will try to describe
current research efforts related to new
diagnostic perspectives in DM type II.
Hopefully, I will be able to emphasize most
important findings related to the possible early
detection of disease.
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DIABETES MELITUS TYPE II (T2D)
Costly healthcare burden and a major cause of
morbidity and mortality due to coronary heart
disease, cerebrovascular disease, peripheral
vascular disease
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T2D common endocrine disease strongly
determined by inheritable factors, is likely
polygenic Develops from chronic and
progressive loss of insulin secretion on a
background of chronic and often progressive
insulin resistance ? Hepatic glucose
overproduction and diminished glucose uptake by
muscle tissues ? Reduced insulin and increased
glucagon secretion Dyslipidemia Reduced
GLP-1 release, diminished incretin response
DIABETES MELLITUS TYPE II (T2D)
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MAJOR RISK FACTORS FOR
T2DFamily history of diabetes (ie, parents or
siblings with diabetes) Obesity (gt20 over
desired body weight or body mass index gt27
kg/m2)(Sedentary life style, active and passive
smoking)Race or ethnicity with high risk of
diabetes (eg, African American, Hispanic
American, Native American, Asian American,
Pacific Islander) Age gt45 years
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Previously identified impaired fasting glucose
or impaired glucose tolerance
Hypertension (gt140/90 mmHg)
Hyperlipidemia HDL cholesterol level lt 0.90
mmol/L or triglyceride level gt2.82 mmol/L,
or both
History of gestational diabetes or delivery of a
baby over (4.1 kg)
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Separate genetic defects ( responsible for the
predominance of one mechanism over the other).
Environmental factors Glucose toxicity has
been shown to contribute to the development of
insulin resistance and impaired insulin secretion
in animal models of diabetes Hyperglycemia
is responsible for some of the resistance and
some of the impairment in beta-cell function
Lipotoxicity
FACTORS CONTRIBUTING TO THE LOSS OF
BETA CELL FUNCTION AND INSULIN RESISTANCE
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INCRETIN HORMONES
Effects of GLP in beta cells Increase in
cell proliferation Stimulation of insulin
synthesis Increase in beta cell mass
Preservation of cells(animals)
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Diabetes type II Is prevention
possible Focus today 1.Understanding the
relationship between clinical progression(based
on circulating glucose levels) and biological
progression (based largely on changes in the
relationship between insulin supply and demand)
of the disease.(Assesment of insulin resistance
and beta cell function) Possible approach
intravenous glucose tolerance test2.Recognition
of prediabetes and early diabetes phase (due to
asymptomatic preclinical phase of disease)
Detection of loss of first-phase insulin release
(point at which glucose intolerance begins to
develop)
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Diminished first-phase insulin secretion is an
early marker of beta cell dysfunction, appearing
long before significant changes in absolute
glucose concentrations are apparent
Elevated postprandial glucose concentrations in
these individuals, despite relatively normal
fasting glucose levels
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Independant risk factor for cardiovascular
diseaseIncreases earlier and faster than
plasma glucose levelsContributes more to HbA1c
than to fasting glucose at A1c levels below
8,5Rate limiting factor for achieving
adequate glycemic control Harmful acute
effectsEndothelial dysfunction
Increase in oxidative stressIncreases
the inflammatory milieu Increase in protein
glycosylationCoagulation affected
POSTPRANDIAL HYPERGLYCEMIA
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Beta cells began to fail 12 years before official
diagnosis
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STANDARD REFERENCE TESTS IN DIAGNOSISThe
fasting plasma glucose (FPG) test (7 mmol/L)
2-hour postload plasma glucose test (11,1
mmol/L)(Both tests require a second
confirmation) Hemoglobin A1c
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ADA 1997 DIAGNOSTIC CRITERIA
FOR T2DSymptoms of diabetes and RPG gt (11.1
mmol/L)       or FPG gt (7.0 mmol/L)
2-hour plasma glucose gt (11.1 mmol/L)
during an OGTT FPG, OGTT, oral glucose
tolerance test RPG Debate FPG or OGTT?
Which is a better predictor of diabetic
complications??? Positive screening test
result- confirmatory test needed (FPG or OGTT RPG
when symptoms related to diabetes are present
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Questionnaires (rule out diabetes with a
good certainty. poor positive predictive values)
Fasting plasma glucose(FPG) ADA- the
screening test of choiceRandom plasma
glucose(RPG) (measuring plasma glucose without
regard to the last food intake). RPG (8.9
mmol/L) or above to be abnormalOral glucose
tolerance test (OGTT) (2 hours after ingestion
of a glucose load of 75 g a plasma glucose value
of 11.1 mmol/L) or more is abnormal
Glycosylated hemoglobin (HbA1c) Different
cutoofs( HBA1c value of 7.0, as the cutoff for
detecting "treatment-requiring diabetes .,other
suggestions 6,5,6 Current view
lowest possible A1C, without unacceptable
hypoglycemia Urinalysis and fingerstick glucose
not to be used in screening!!!
SCREENING FOR TYPE II DIABETES
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PROBLEMS RELATED TO SCREENINGPopulation MUST
have one or more indications for screening
Choice of screening test FPG or RPG, rarely
HbA1c Current screening methods for type 2
diabetes and pre-diabetes are inadequate
Problems related to their inconvenience and
inaccuracy
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Average Blood Glucose Instead of HbA1c?
Diabetes Care (2007)Reporting
glycohemoglobin results as an A1c-derived average
glucose, said Nathan, would have the advantage of
reporting chronic glycemia in the same units as
the patients' self-monitoring of daily
glycemiaStrong mathematical relationship
between average glucose and HbA1c, but if a
switch is to be made from HbA1c to average
glucose levels, an international study is needed
to establish the relationship across diabetes
type, races, and ethnicities, said Nathan
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New technologies in screeningdiabetes
complications
AGE (dermal advanced glycation end products)
Spectroscopic measurement of dermal AGEs
(SAGE) People with diabetes have fluorescent
deposits on their skin(area of skin near the
elbow) Based on skin fluorescence caused by
AGEs Possible quantification of diabetes
risk score, prediction of future diabetic
retinopathy and nephropathy Advantages No
fasting, no biohazards, automatical compensation
for subject-specific skin differences, immediate
result.
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PREDICTIONS FOR THE DEVELOPMENT OF T2D IN HIGH
RISK INDIVIDUALS The fasting and 2-h glucose
levels at baseline HbA1C

Insulin sensitivity
Insulin
secretion Continued decrease in insulin
sensitivity and ß-cell function (i.e., insulin
secretion relative to sensitivity) observed
PROINSULIN (fasting)Measure of insulin
sensitivity and not ß-cell function.Good
marker of risk of progression to diabetes, with
higher proinsulin levels at baseline resulting
in the greater risk
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Usually conducted on subjects with IGT (impaired
glucose tolerance)
.MINIMAL MODEL
2. BIGTT MODEL Possible to do simultaneous
measurement of insulin sensitivity and insulin
response from a single clinically applicable
protocol Possible to define the "disposition
index, an important index of ß-cell
functionality and a predictor of impaired
glucose tolerance and diabetes
PREVENTION TRIALS
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ESTIMATION OF INSULIN SECRETION 1) the
corrected insulin response (CIR) (100 30-min
insulin)/(30-min glucose 30-min glucose - 70
mg/dl) 2) the insulin-to-glucose ratio (IGR)
(30-min insulin - fasting insulin)/(30-min
glucose - fasting glucose) IGR and CIR were
highly correlated at baseline (Spearman r
0.95) ESTIMATION OF INSULIN SENSITIVITY 1)
Fasting insulin 2) The insulin sensitivity
index (ISI), which is ISI 22.5/(fasting
insulin fasting glucose/18.01), ISIs
reciprocal is the homeostasis model assessment of
insulin resistance. ISI and 1/fasting insulin
were, as expected, highly correlated at baseline
(Spearman r 0.99)
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ASSESMENT OF INSULIN RESISTANCE AND BETA CELL
DISFUNCTION -Intravenous glucose tolerance
test-Disposition index (DI) as a measure of the
overall ability of the glucose regulating system
to renormalize glycemia after perturbation by
nutrient intake. DIAIRGLUCOSESI-Reduced
DI is a harbinger of type 2 diabetes-Emerging
consensus that reduced ß-cell function as
reflected in the DI is the strongest predictor of
type 2 diabetes in at-risk populations
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DOES THIS REDUCED ISLET FUNCTION HAVE A GENETIC
COMPONENT?
-A strong genetic basis for disease -Inheritance
of ß-cell function suggested -Locus on
chromosome 11 related to diabetes risk and linked
with the DI -Inheritance of reduced DI,
possible contributor to increased genetic risk
for type 2 diabetes
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OTHER TYPES OF MARKERS IN DETERMINING
THE RISK OF DEVELOPMENT OF
T2D Inflammatory and immunological markers
(blood) C-reactive protein (CRP) serum
amyloid A interleukin-6 RANTES Macrophage
migration inhibitory factor (MIF) Soluble
intercellular adhesion molecule Low-grade
inflammation and immunological activation may be
elevated in patients at high risk of diabetes.(Dr
Herder group)
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THE RATIONAL BEHIND USE OF
IMMUNOLOGICAL MARKERS Increased numbers of
macrophages exist in the islets of type II
diabetes patientsAssociated with development
of type II diabetes Activation of the immune
system in obesity is a risk factor for the
development of type II diabetes
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GENETIC MARKERS IN T2D Clinical
indications Determine those at higher risk for
T2D, above 140 RESULTS SO FARGenes
responsible for monogenic forms of diabetes
(notably, maturity-onset diabetes of the young),
and, in patients presenting with early-onset
diabetes, identified Gene identification for
more common, multifactorial forms of T2D slower.
Common variants in the PPARG, KCNJ11 and CAPN10
genesinfluence T2D-susceptibility (particularly
in individuals with other risk factors) Genes
have been identified on chromosomes 1q, 12q, 20q,
and 17q
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PPAR (Peroxisome proliferator-activated receptor
gamma) G3p25,frequency of allele 85., key
regulator of adipocyte development and
function KCNJ11 (Potassium inwardly rectifying
channel, subfamily J, member 11) 11p15, E23K.,
1.2 .,40 Component of the beta-cell KATP
channel CAPN10 (Calpain 10) 2q37, 1.2., 1025
(SNP44) Protease of uncertain function implicated
in insulin secretion TCF1 (HNF1A) Hepatocyte
nuclear factor 1-alpha transcription factor
1 12q22-qter., 20.,Transcription factor in
beta-cell (and other tissues) HNF4 (Hepatocyte
nuclear factor 4-alpha) A20q12?, ??????? I IRS1
(Insulin receptor substrate 1) 2q36., 1.25 .,
710 Central molecule in insulin signalling
cascade
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GENES AND PREDICTION OF DIABETES1.
TCF7L2 (transcription factor 7-like 2, linkage
region on 10q) present in European,
Chinese, USA population, highly replcated in
Caucasian and African population Associated
with onset of diabetes condition in younger
populationIncreases the chances of diabetes in
individuals with impaired glucose
toleranceTest for diabetes risk
TCF7L2 variants are associated with impaired
beta-cell function but not with insulin
resistance Chances of diabetes are
increased by 50 if one gene variant If
two copies of gene variant are carried/increase
of 100 Routine genetic testing for these
variants still not recommended!
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OTHER GENES KCNJ11 Association T2D and
hypertension (Korean population) ARHGEF11
-chromosome 1q, associated with insulin
resistance andT2D (Pima Indians) Mutations in
the NeuroD/BETA2 gene assocated with T2DFABP2-
50 Americans (FABP2 causes the food to be
metabolized in a way that interferes with the
bodys ability to get rid of the excess sugar in
the blood stream, resulting in diabetes. It is
not yet the established cause of diabetes)A
minor role for some of the gene products involved
in insulin secretion or insulin action, such as
IRS-1, the glucagon receptor, the sulphonylurea
receptor (SUR),the peroxisome proliferator
activated receptor- (PPAR), and the MAPKBIP1
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LIVER MARKERS AND RISK OF SUBSEQUENT
DIABETES Associations between these markers and
diabetes risk were independent of directly
measured insulin sensitivityRaised liver
markers in this context reflect hepatic IRSo
far, no association between ALP concentrations
and diabetes risk, (possible lack of specificity
of ALK i indicating liver disease) Five
studies have assessed the diabetes risk
associated with elevated GGT, and in four of
these studies, the association with diabetes was
statistically significant after adjustment for
potential confounders
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Markers of liver injury, including AST and ALT,
were significantly associated with risk of
incident type 2 diabetes, independently of
classical predictors, CRP, and the metabolic
syndrome in middle-aged Caucasian men of average
BMI. (Adjustment for a broad spectrum of type 2
diabetes risk factors, including directly
measured insulin sensitivity and secretion was
made). Men with baseline ALT levels 29 units/l
had more than three times the risk for diabetes
than men with ALT lt17 units/l (alcohol intake and
CRP excluded as potential confounders). Study not
applicable to woman population ALT cutoff to-
potential in diabetes prediction
algorithms NAFLD or related pathologies may
predispose to type 2 diabetes
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OTHER MARKERS MCH-melanine
concentrating hormone Neuropeptide found in
the brain Expressed in the mammalian
hypothalamus and involved in the regulation of
food intake and energy balance Increases
secretion of insulin Boosts the development of
beta cells Stimulates appetite
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RETINOL BINDING PROTEIN (RBP4) RBP-4
levels are an important marker for type 2
diabetes (Beth Israel Deaconess Medical
Center) Higher levels of protein found in people
with -higher body mass index
-higher triglicerides -decrease
in HDL
-increase in BP -prediabetes

-diabetes -family history of diabetes Associated
with rise of insulin resistance (fat cells start
making a lot of RBP4) Animal studies showed
RBP-4 can cause insulin resistance
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OSTEOCALCIN Gerard Karsenty et ass. of
the Columbia University Medical Center, showed
that osteocalcin, a protein secreted by bone
cells, regulates insulin production and insulin
sensitivity in the body Both in vitro studies
and in vivo studies on knockout mice show that
osteocalcin stimulates beta cells to produce
insulin and promotes the growth of new beta cells
in the pancreas Osteocalcin signals fat cells
to produce adiponectin, a metabolic hormone that
regulates insulin sensitivity Osteocalcin
involved in glucose regulation is the
non-carboxylated fraction of osteocalcin (Most
osteocalcin in the bone matrix is carboxylated)
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NEW MARKERS Signaling defects(altered
insulin-stimulated glucose transport activity)
Protein tyrosine phosphatase 1B (PTB1B)
deficiency reduces insulin resistance and the
diabetic phenotype in mice with polygenic insulin
resistance Reduced mitochondrial function may
predispose the individuals to intramyocellular
lipid accumulation and insulin resistance
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PROMISING RESULTS 1.S-adenosyl
methionine(SAM) S-adenosyl Methionine is
decreased in erythrocytes of diabetic patients.
SAM involved in propagation of insulin
resistance Decrease associated with disease
progression 2.Prenatal glucose and insulin levels
Important risk factors in developement of T2D
later in life, (independent of the maternal type
of diabetes and therefore independent of genetic
predisposition) Presence of a cellular memory
in insulin target tissues implied!
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THANK YOU FOR YOUR ATTENTION!