emad hamed.insulin resistance idf

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Insulin Resistance From Theory to Therapy

Presented by: Dr. Emad Hamed

Practicing Physician, Naga- Hammady

Best of IDF

Why Insulin Resistance ?

Although it is a well known and documented condition for

years; I think it is still a vague issue in the minds of many

Practicing Physicians.

We want to point out the role of IR in T1DM, hypertension,

PCOS and other conditions.

It is important to clarify that IR is a measurable parameter and

it's measurement is easy, practical and very useful in

understanding the underlying pathogenesis of different

conditions and consequently their management.

Presentation Topics

Background

Assessment of Insulin Resistance

Epidemiology

Type 1 Diabetes

Insulin Resistance & Metabolic Syndrome

Metabolic Syndrome (MS)

MS in Persons with IFG & IGT

Presentation Topics

IR & the Liver

OBESITY

IR & Hypertension

IR & Vit. D

IR & PCOS

IR & Other Issues ( Spleen – Psoriasis )

Management of IR

Prevention of Diabetes

Background

The syndromes of insulin resistance actually make up a

broad clinical spectrum, which includes obesity, glucose

intolerance, diabetes, and the metabolic syndrome, as

well as an extreme insulin-resistant state.

Many of these disorders are associated with various

endocrine, metabolic, and genetic conditions.


In theory, insulin sensitivity can be assessed through the

following methods:

Fasting insulin level Measurement of response to direct

intravenous infusion of insulin.

Euglycemic insulin clamp technique.

“These 2 tests are accurate, but they are research tools

and are not routinely used in clinical practice”.

Homeostatic model assessment for insulin resistance

(HOMA-IR)

• = fasting glucose (mg/dL) X fasting insulin (uU/mL) / 405

• = fasting glucose (mmol/L) X fasting insulin (uU/L) / 22.5.

• A value greater than 2 indicates insulin resistance.

Quantitative Insulin Sensitivity Check Index (QUICKI).

They both correlate reasonably well with the euglycemic

clamp technique.


Epidemiology

The mean HOMA-IR score of the subjects from urban

community were statistically greater than that of the

subjects from rural community.

The prevalence of insulin resistance in urban community

and rural community were 64% and 2% respectively.

( P-1393, Nigeria )

Epidemiology

A study was done to examine Insulin Resistance among 5-

15 years old children from an urban area of Sri Lanka.

Although many children were able to control glucose

within normal limits, they had very high levels of insulin

secretion denoting that insulin resistance is developing

form a very young age. Those who were of low birth

weight but obese as children had the highest risk of

developing insulin resistance.

( O-0434, Sri-Lanka )

Epidemiology

A study was done to assess IR in diabetic people as well in

healthy controls and to find out it's association with the

components of MS in Nepal.

C-peptide levels and insulin resistance are closely associated

with the components of MS in healthy individuals as well as in

diabetic people.

( P-1392, Nepal )

Type 1 DM

MS is a frequent finding in Type1 DM and it's presence

is associated with poor metabolic control and more

micro and macro vascular complications.

MS was associated with increased IR estimated by

eGDR.

( D-1108, Spain)

Obese Type1 patients may as well show insulin

resistance. The amount of insulin can be significantly

reduced through additional treatment with Metformin

and DPP4 inhibitors.

( P- 1402, Germany )

IR & Metabolic Syndrome

Insulin resistance plays a major pathogenic role in the development of the metabolic syndrome, which may include any or all of the following:

Hyperinsulinemia

Type 2 diabetes or glucose intolerance

Central obesity

Hypertension

Dyslipidemia that includes high triglyceride levels

Low HDL-C level and small, dense low-density lipoprotein (LDL) particles

Hypercoagulability characterized by an increased plasminogen activator inhibitor–1 (PAI-1) level.

Metabolic Syndrome

Metabolic syndrome (MS) is defined by cluster of

cardiovascular risk factors which to a greater extent is

influenced by ethnicity. Many definitions have been

suggested since the inception of this syndrome which has

created uncertainty among physicians.

To determine the frequency of metabolic syndrome in type

2 D.M according to three commonly used operational

definitions (WHO, NCEP ATP III and IDF) and to evaluate

the agreement between these classifications in Pakistani

cohort.

Metabolic Syndrome

A study was done to examine the relationship between

reduction in insulin resistance and various metabolic

parameters in patients with metabolic syndrome.

Data obtained show that insulin sensitizing therapy

significantly changes SUA levels and other metabolic

parameters; all this strongly depends on the degree of

the reduction in insulin resistance.

( P-1408, Georgia )

Metabolic Syndrome

This study results suggest that NCEP (ATPIII) and IDF are

the most reliable criteria for diagnosing metabolic

syndrome in type 2 diabetic patients, with NECP capturing

more patients in comparison to IDF definition.

The alarmingly high frequency of metabolic syndrome in

type 2 diabetes found in this study suggests that primary

prevention strategies should be initiated early in this ethnic

group and our health care system should be geared up to

cope with this deadly condition.

( P-1400, Pakistan )

Metabolic Syndrome

A study was done to examine the difference in prevalence

of Metabolic Syndrome in populations of Albania in

confront of the Italians and Peruvians.

They conclude that in all three population the prevalence

of metabolic syndrome among young healthy people is

important and the risk factors are almost the same with a

difference for low HDL level that is found very often

amongst Albanian.

( P-1412, Albania )

Metabolic Syndrome

Metabolic Syndrome in obese women was frequent

especially after menopause, thus multiple cardiovascular

risk factors are added so a particular attention is needed to

avoid serious complications.

( P-1404, Tunisia )

Metabolic Syndrome

The aim of this paper was to examine the relationship

between time spent in sedentary behavior and metabolic

syndrome using meta-analysis.

Current results, emphasize the importance of reducing

sedentary behaviors, such as TV viewing and time on the

computer, for the prevention of metabolic syndrome.

( D-0817, UK )

Metabolic Syndrome

Waist circumference (WC) is a convenient measure of

abdominal adipose tissue and it is a risk factor for

cardiovascular diseases (CVD) and diabetes.

The cutoff points for WC are higher in women than the

currently recommended 80cm for Sub-Saharan

populations, whilst in men it is lower. Of importance is

that the cutoff points are reversed in this population for

the genders.

These results emphasize the importance of establishing

ethnic based values to correctly identify subjects with the

metabolic syndrome.

( D-1110, South Africa )

MS in Persons with IFG & IGT

The prevalence of MS in persons with either IFG or IGT

was twofold that encountered in the general population,

while in individuals with both IFG and IGT it is similar

to that found in patients with type 2 diabetes mellitus.

Therefore IFG and IGT should not be approached as

isolated conditions because often are associated with

other features of the MS that, individually and

interdependently, are responsible for a substantial

increase in cardiovascular morbidity and mortality.

( P-1399, Romania )

IR & the Liver

The liver has a central role in the regulation of

circulating glucose concentrations. During fasting,

glucose is produced mainly by the liver as a result of

increased glycogenolysis and gluconeogenesis (GNG).

During postprandial state the impaired suppression of

hepatic glucose production (HGP), due to the presence

of hepatic insulin resistance, determines high glucose

concentrations.

IR & the Liver

Insulin acts at the level of the liver through a direct

and/or indirect effect (i.e. on glucose transport and/or

intracellular enzymes). Insulin resistant (IR) subjects

have increased fasting GNG, but fasting glucose

concentration remains within normal ranges, as well as

HGP, because of a compensatory decrease in

glycogenolysis.

IR & the Liver

When T2DM develops, the hepatic autoregulation is

lost, increased GNG and glycogenolysis determine the

increase in HGP that explains fasting hyperglycemia.

In conclusion, the liver plays a determinant role in the

pathogenesis of T2DM.

( S-103, Italy )

IR & the Liver

Ectopic fat deposition in the liver is associated with

metabolic abnormalities, including insulin resistance,

dyslipidemia and diabetes.

Non-alcoholic fatty liver disease (NAFLD) is defined as

increased liver fat in individuals who do not drink

excessive alcohol and who do not have other causes for

liver disease.

IR & the Liver

A subset of patients with NAFLD have non-alcoholic

steatohepatitis (NASH) characterized by lobular

inflammation and evidence of cellular damage with or

without fibrosis.

While simple steatosis is considered relatively benign,

NASH can progress over time to cirrhosis.

( S-114, USA )

IR & the Liver

A study was done to assess the effect of Orlistat

(Gastrointestinal lipase inhibitors) + Metformin vs Metformin

alone in Nondiabetic Patients with Insulin Resistance and

Nonalcoholic Steatohepatitis (NASH)

Orlistat (Gastrointestinal lipase inhibitors) therapy and dietary

counseling were associated with significant decreases in

NASH.

( O-0439, Venezuela )

IR & the Liver

Nonalcoholic fatty liver disease (NAFLD) does not seem

to be associated with MS in Bangladeshi population as

defined through the 3 major criteria provided by IDF,

ATP III and WHO.

Various components of MS are associated with NAFLD

among which central obesity, dysglycemia and

dyslipidemia are the most significant ones. However,

they do not seem to cluster in the manner as predicted by

IDF, ATP III and WHO

( P-1384, Bangladesh )

IR & the Liver

Several prospective studies have shown that fat

accumulation in the liver due to non-alcoholic causes

(NAFLD) precedes and predicts type 2 diabetes,

cardiovascular disease and NASH independent of obesity

and fat distribution.

The study suggested that avoidance of excess simple

sugar intake may be an important factor in the prevention

of progressive deterioration in glycemic control in type 2

diabetes due to worsening hepatic insulin resistance and

of NASH.

( M 108, Finland)

OBESITY

Hypertrophic

• Fat storage lead to

inappropriate cellular

enlargement

• Metabolically ..

• Genetically determined

• 4 times more in FDR of

diabetics

• Related to the development

of DM

Hyperplastic

• Fat storage lead to

recruitment of new

adipose cells

• Metabolically Normal

(Abstract: 81, Sweden)

OBESITY

Visceral fat-derived protein " Visfatin" plasma levels

correlates strongly with the amount of visceral adipose

tissue in humans.

It has high significant correlation with HOMA IR and

other parameters linking Visceral fat to IR, DM and

obesity.

( D- 1112, Egypt )

IR & Hypertension

Hypertensive diabetics have significant insulin

resistance and higher fasting insulin levels when

compared to normotensive counterparts.

Though complications were higher in the same group

they were not statistically significant.

Diabetic patients with hypertension should be treated

more aggressively and evaluated for complications.

( D-1111, India )

Elevated values of heart rate and insulin resistance reflect

enhanced sympathetic nervous system activity and may

be connected with development of coronary artery

disease and diabetes.

24-h double product calculated as systolic blood pressure

and heart rate and body mass index may be

complementary parameters in prediction of insulin

resistance in hypertensive nondiabetics with coronary

artery disease.

( P-1386, Poland )

IR & Hypertension

Insulin Resistance & Hypertension

Nigerian hypertensives have greater HOMA-estimated

insulin resistance than their normotensive counterparts.

This finding implies that hypertensive patients should

have regular screening for diabetes mellitus and other

categories of glucose intolerance as the increased insulin

resistance seen in them will increase their risk of

developing type 2 diabetes mellitus.

( P-1387, Nigeria )

Vitamin D supplementation improved insulin resistance

after a single large dose of Vitamin D in South Asians.

Vitamin D deficiency may explain the higher prevalence

of diabetes and metabolic syndrome in South Asian

population.

( D-0820, UK )

Circulating osteocalcin level is associated with improved

glucose tolerance, insulin secretion and sensitivity

independent of the plasma adiponectin level in human.

( D-1109, Korea )

IR & Vit. D

IR & PCOS

Routine measurement of WC in patients with PCOS and normal body

mass can be a marker of IR, type 2 diabetes mellitus, arterial

hypertension and cardiovascular diseases.

(P-1397, Uzbekistan)

Recent studies indicate the possible role of vitamin D in the

pathogenesis of IR and glucose metabolism.

Women with PCOS have mostly insufficient 25-OH-D levels, and

25-OH-D replacement therapy may have a beneficial effect on IR in

obese women with PCOS.

(P-1383, India)

Hyperandrogenemia and insulin resistance in PCOS may have an

inherited basis and these are likely to be associated with the disorder

as independent traits.

(P-1410, Bangladesh)

IR & Other Conditions

A study was done to examine the spleen as a major

source of inflammation-induced insulin resistance in

obesity.

Spleen has a potential role on metabolism, as its surgical

removal causes protection against obesity-induced

inflammation and insulin resistance, enhanced by

reduction on macrophage migration to metabolic tissues.

(D-0819, Brazil)

IR & Other Conditions

Psoriasis (Ps) is a chronic autoimmune disease which affects

the skin and joints. Adipocytokines may play an important

role in the physiopathology of psoriasis lesions and

pathogenesis of impaired fasting glucose (IFG)

The secretory dysfunction of proinflammatory and anti-

inflammatory adipocytokines represent the main link

between IFG and Ps.

Weight loss and exercise have been reported to significantly

increase adiponectin and decrease leptin levels.

Body weight loss and exercise could potentially become part

of the general management of Ps in patients with IFG.

(P-1395, Romania)

Management of IR

Metformin in T2D & Prediabetes

Metformin is a biguanide; it reduces hepatic glucose

output and increases the uptake in the peripheral tissues

(muscle and adipocytes).

Metformin is a major drug in the treatment of patients

who are obese and have type 2 diabetes. The drug

enhances weight reduction and improves lipid profile

and vascular integrity.

Management of IR

Metformin in T2D & Prediabetes

Metformin in patients with T2D and prediabetes reduces

insulin resistance, especially at patients with IFG and

IGT, improves glycemic and lipid control, decreases

cytokines connected with insulin sensitivity.

(D-0821, Russia)

A study to evaluate the effect of exenatide and metformin

on the insulin resistance variation after 3 months of

treatment in type 2 diabetes patients receiving insulin.

This study confirm that association of exenatide + insulin

treatment at obese T2DM patients seems to decrease the

total insulin daily dose, but the insulin resistance compared

for the group treated with metformin and the group treated

with exenatide seems to be not statistically different.

(P-1380, Romania)

Management of IR

Exenatide & metformin

Management of IR

Dietary omega-3 (PUFAs)

Omega-3 PUFAs administered exert a number of

beneficial effects on diabetes associated metabolic

disorders (glycemic control, FFA, antioxidative defense),

attenuate IR parameters,

increase plasma adiponectin and decrease osteoprotegerin

levels thus lowering cardiovascular risk of T2Ds

(P-1403, Ukraine & Netherlands)

Management of IR

Exenatide & glimepiride

A multicenter, randomised, single-blind study on the

effects of exenatide or glimepiride on insulin resistance

in patient intolerant to metformin at maximum dose.

Exenatide and glimepiridel improved diabetes control

when added to metformin, but only Ex improved insulin

resistance related-parameters.

(D-0815, Italy)

Management of IR correction with fetal

stem cells in metabolic syndrome Results:-

IR Reduction, insulin-sensitivity restoration in all

groups.

Reduction of basal and stimulated hyperinsulinemia in

IGT-group

Reduction of serum C-peptide

Other effects: reduced glycemia, lipid count, weight loss,

blood pressure decrease.

Conclusions:-

In MS, TFSC ( Transplantation of Fetal Stem Cell )

results in reliable subsidence of IR symptoms.

(P-1391, Ukraine)


Alfa Glucosidase

The STOP-NIDDM trial demonstrated The STOP-

NIDDM trial demonstrated that the alpha-glucosidase

inhibitor acarbose reduced the risk of diabetes by 25% in

subjects with

It is suggested that the effect of acarbose on the

prevention of diabetes in subjects with IGT was in part

mediated by an effect on the disposition index, thus an

improvement in insulin secretion adjusted for insulin

resistance.

(O-0440, Canada)

Pharmacologic intervention with medications that reverse

known pathophysiologic abnormalities - beta cell dysfunction

and insulin resistance - uniformly prevent IGT progression

toT2DM. (DREAM, DPP, TRIPOD, PIPOD, ACT NOW)

Metformin in the US DPP and Indian DPP reduced the

development of T2DM by ~30% and has been recommended

by the ADA.

Metformin consistently reduces the rate of conversion of IGT

to T2DM.

(Abstract: 49, USA)



A recent analysis of the 10 year follow up of the DPP

demonstrated that metformin treatment was highly cost

effective in diabetes prevention.

Pharmacologic intervention with a variety of agents

(thiazolidinediones, metformin, acarbose, GLP-1

analogues) consistently reduces the rate of conversion of

IGT to T2DM.

( Abstract: 49, USA)

emad hamed.insulin resistance idf

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