Best of IDF Insulin Resistance From Theory to Therapy Presented by: Dr. Emad Hamed Practicing Physician, Naga- Hammady
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 its 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 ResistanceIn theory, insulin sensitivity can be assessed through thefollowing methods:Fasting insulin level Measurement of response to directintravenous infusion of insulin.Euglycemic insulin clamp technique.“These 2 tests are accurate, but they are research toolsand are not routinely used in clinical practice”.
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.
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 its 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 its 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 SyndromeInsulin resistance plays a major pathogenic role in thedevelopment of the metabolic syndrome, which may include anyor 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 plasminogenactivator 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 Hyperplastic•Fat storage lead to •Fat storage lead toinappropriate cellular recruitment of new adiposeenlargement cells•Metabolically .. •Metabolically Normal•Genetically determined•4 times more in FDR ofdiabetics•Related to the developmentof DM (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 )
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 )
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 )
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 )
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)
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)
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 syndromeResults:-IR Reduction, insulin-sensitivity restoration in all groups.Reduction of basal and stimulated hyperinsulinemia inIGT-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)
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)
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)