This document discusses insulin resistance (IR) and its relationship to various medical conditions. It begins by defining IR and describing methods to assess it, then discusses its epidemiology and links to type 1 diabetes, metabolic syndrome, obesity, hypertension, polycystic ovarian syndrome (PCOS), and other issues. Management of IR focuses on lifestyle changes, diet, exercise and medication when needed. Prevention of diabetes is also emphasized given IR's role in increasing risk.

1. ‫بسم ا الرحمن‬
‫الرحيم‬
‫ل‬
‫ول ت سبن لذ ن قتل ف سب ل ّ‬
‫َ َ َحْ َ َ ّ اّ ِي َ ُ ِ ُوا ِي َ ِي ِ ا ِ‬
‫َمْ َاًا َلْ َحْ َا ٌ ِنْ َ َّ ِمْ ُرْ َ ُو َ *‬
‫أ و ت ب أ ي ء ع د ربه ي زق ن‬
‫صدق ا العظيم‬

2. Best of IDF
Insulin Resistance
From Theory to Therapy
Presented by: Dr. Emad Hamed
Practicing Physician, Naga- Hammady

3. 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.

4. Presentation Topics
 Background
 Assessment of Insulin Resistance
 Epidemiology
 Type 1 Diabetes
 Insulin Resistance & Metabolic Syndrome
 Metabolic Syndrome (MS)
 MS in Persons with IFG & IGT

5. Presentation Topics
 IR & the Liver
 OBESITY
 IR & Hypertension
 IR & Vit. D
 IR & PCOS
 IR & Other Issues ( Spleen – Psoriasis )
 Management of IR
 Prevention of Diabetes

6. 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.

7. Assessment of Insulin
Resistance
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”.

8. Assessment of Insulin
Resistance
 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.

9. 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 )

10. 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 )

11. 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 )

12. 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 )

13. 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.

14. 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.

15. 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 )

16. 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 )

17. 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 )

18. 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 )

19. 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 )

20. 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 )

21. 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 )

22. 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.

23. 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.

24. 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 )

25. 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.

26. 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 )

27. 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 )

28. 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 )

29. 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)

30. OBESITY
Hypertrophic Hyperplastic
•Fat storage lead to •Fat storage lead to
inappropriate cellular recruitment of new adipose
enlargement cells
•Metabolically .. •Metabolically Normal
•Genetically determined
•4 times more in FDR of
diabetics
•Related to the development
of DM
(Abstract: 81,
Sweden)

31. 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 )

32. 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 )

33. IR & Hypertension
 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 )

34. 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 )

35. IR & Vit. D
 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 )

36. 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)

37. 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)

38. 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)

39. 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.

40. 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)

41. Management of IR
Exenatide & metformin
 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)

42. 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)

43. 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)

44. 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)

45. Prevention of Diabetes
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)

46. Prevention of Diabetes
 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)

47. Prevention of Diabetes
 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)