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بسم الله الرحمن الرحيم
صدق الله العظيم
Insulin ResistanceFrom Theory to Therapy
Presented by: Dr. Emad HamedPracticing 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.
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”.
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.
Assessment of Insulin Resistance
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:HyperinsulinemiaType 2 diabetes or glucose intoleranceCentral obesityHypertensionDyslipidemia that includes high triglyceride levelsLow HDL-C level and small, dense low-density lipoprotein (LDL) particlesHypercoagulability 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 IRMetformin 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 IRMetformin 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 IRExenatide & metformin
Management of IRDietary 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 IRExenatide & 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-groupReduction of serum C-peptideOther 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)
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)
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)
Prevention of Diabetes
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)
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