prediction of diabetes mellitus type ii

• 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 chroni

PREDICTION OF DIABETES

MELLITUS TYPE II

-NEW DIAGNOSTIC PERSPECTIVES-

Adlija Jevric-Causevic

Faculty of Pharmacy, University of Sarajevo

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.

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

• 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)

MAJOR RISK FACTORS FOR T2D

• Family history of diabetes (ie, parents or siblings with diabetes)

• Obesity (>20% over desired body weight or body mass index >27 kg/m2)

(Sedentary life style, active and passive smoking)

• Race or ethnicity with high risk of diabetes

American, Pacific Islander)

• Age >45 years

• Hypertension (>140/90 mmHg)

• Hyperlipidemia

HDL cholesterol level < [0.90 mmol/L]

or triglyceride level >[2.82 mmol/L], or both

• History of gestational diabetes or delivery of a baby over (4.1 kg)

• Previously identified impaired fasting glucose or impaired glucose tolerance

• 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

INSULIN RESISTANCE

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)

Diabetes type II – Is prevention possible

Focus today 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 test

2.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)

•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

•Independant risk factor for cardiovascular disease

•Increases earlier and faster than plasma glucose levels

•Contributes more to HbA1c than to fasting glucose at A1c levels below 8,5%

•Rate limiting factor for achieving adequate glycemic control

Harmful acute effects

•Endothelial dysfunction •Increase in oxidative stress

•Increases the inflammatory milieu •Increase in protein glycosylation

•Coagulation affected

POSTPRANDIAL HYPERGLYCEMIA

Beta cells began to fail 12 years before official diagnosis

STANDARD REFERENCE TESTS IN

DIAGNOSIS

•The 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

ADA 1997 DIAGNOSTIC CRITERIA

FOR T2D

•Symptoms of diabetes and RPG > (11.1 mmol/L)

• 2-hour plasma glucose > (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

*Questionnaires

(rule out diabetes with a good certainty poor positive predictive values)

ADA- the screening test of choice

(measuring plasma glucose without regard to the last food intake).

RPG (8.9 mmol/L ) or above to be abnormal) or above to be

(2 hours after ingestion of a glucose load of 75 g a plasma glucose value of 11.1 mmol/L) or more is

abnormal

Different cutoofs( HBA1c value of 7.0%, as the cutoff for detecting "treatment-requiring diabetes 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

PROBLEMS RELATED TO SCREENING

•Population MUST have one or more indications for screening

•Choice of screening test: FPG or RPG, rarely HbA1c FPG or RPG

•Current screening methods for type 2 diabetes and

pre-diabetes are inadequate

•Problems related to their inconvenience and inaccuracy

Average Blood Glucose Instead of HbA1c?

Diabetes Care (2007)

Reporting glycohemoglobin results as an A1 c -derived average

glucose, said Nathan, would have the advantage of reporting chronic glycemia in the same units as the patients' self-monitoring of daily glycemia

Strong mathematical relationship between average glucose and

levels, an international study is needed to establish the relationship across diabetes type, races, and ethnicities, said Nathan

New technologies in screening

diabetes complications

• 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

PREDICTIONS FOR THE DEVELOPMENT OF

T2D IN HIGH RISK INDIVIDUALS

•Insulin sensitivity •Insulin secretion

Continued decrease in insulin sensitivity and β-cell function (i.e., insulin secretion cell function (i.e., insulin secretion relative to sensitivity) observed

PROINSULIN (fasting)

•Measure of insulin sensitivity and not β-cell function.insulin sensitivity

•Good marker of risk of progression to diabetes, with higher proinsulin risk of progression to diabetes

levels at baseline resulting in the greater risk

•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

ESTIMATION OF INSULIN SECRETION

1) the corrected insulin response (CIR) = (100 × 30-min insulin)/(30- (CIR)

min glucose × [30-min glucose - 70 mg/dl])

2) the insulin-to-glucose ratio (IGR) = (30-min insulin - fasting (IGR)

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]),

ISI´s 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)

ASSESMENT OF INSULIN RESISTANCE AND

BETA CELL DISFUNCTION 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

DI=AIR GLUCOSE ×S I

-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 populationspredictor of type 2 diabetes in at-risk populations

-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 reduced DI

risk for type 2 diabetes

OTHER TYPES OF MARKERS IN DETERMINING THE RISK OF

• 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)

THE RATIONAL BEHIND USE OF IMMUNOLOGICAL MARKERS

•Increased numbers of macrophages exist in the islets of type II diabetes patients

•Associated with development of type II diabetes

•Activation of the immune system in obesity is a risk factor for the

development of type II diabetes

maturity-•Gene identification for more common, multifactorial forms of T2D

influence T2D-susceptibility (particularly in individuals with other risk

factors)

•Genes have been identified on chromosomes 1q, 12q, 20q, and 17q

PPAR ( (Peroxisome proliferator-activated receptor gamma)

G3p25,frequency of allele 85%., key regulator of adipocyte development and function

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);

GENES AND PREDICTION OF DIABETES

1 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 population

•Increases the chances of diabetes in individuals with impaired

glucose tolerance

•Test for diabetes risk Test for diabetes risk

•TCF7L2 variants are associated with impaired beta-cell function but associated with impaired beta-cell function

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!

OTHER GENES

•KCNJ11 –Association T2D and hypertension (Korean population)

•ARHGEF11 -chromosome 1q, associated with insulin resistance and

T2D (Pima Indians)

•Mutations in the NeuroD/BETA2 gene assocated with T2D

• FABP2- 50% Americans FABP2

(FABP2 causes the food to be metabolized in a way that interferes with the body´s 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 forsome of the gene products involved in insulin secretion

or insulinaction, such as IRS-1, the glucagon receptor, the sulphonylureareceptor (SUR),the peroxisome proliferator activated receptor- (PPAR), and the MAPKBIP1

LIVER MARKERS AND RISK OF

SUBSEQUENT DIABETES

•Associations between these markers and diabetes risk were independent

of directly measured insulin sensitivity

•Raised liver markers in this context reflect hepatic IR

•So 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

•Markers of liver injury, including AST and ALT, were significantly associated

associated with risk of incident type 2 diabetes, independently of risk of incident type 2 diabetes

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 <17 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

OTHER MARKERS

• Neuropeptide found in the brain

• Increases secretion of insulin

• Boosts the development of beta cells

• Stimulates appetite

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

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)

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

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 targettissues implied!