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  Français - August 16, 2011
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  Topic  

Insulin Resistance

Insulin resistance is often associated with abdominal obesity, is a factor of the metabolic syndrome and is implicated in the development of atherosclerosis. Insulin resistance together with beta cell dysfunction leads to the appearance and gradual progression of type 2 diabetes. Thiazolidinediones, which act on insulin resistance, can slow and perhaps even prevent the progression of type 2 diabetes, where in some cases insulin injections become necessary. Also, treatment of insulin resistance with thiazolidinediones has been shown to ameliorate several complications associated with insulin resistance, such as hypertension, dyslipidemia, hyperinsulinemia, visceral fat, microalbuminuria and hyperglycemia. The conference presentations in this section will explore in intricate detail the nature of insulin resistance, its causes and consequences.

Presentations listing

Adipocyte-Derived Factors: Effects on Insulin Sensitivity... - Prof. Philipp Scherer
Insulin Resistance in Children and Adolescents with Type 1... - Dr. Thomas Reinehr
Insulin Resistance and Cardiovascular Disease - Pleiotropic... - Dr. Subodh Verma
Obesity and Insulin Resistance: Precursors for Type 2... - Prof. John Prins
Insulin Resistance, Inflammation and Atherosclerosis in... - Prof. Nikolaus Marx
Measuring Insulin in Clinical Practice - Prof. David R. Matthews
Polymorphism -308 G/A of the TNF-(alpha) Gene: Effect on... - Dr. Jose Luis Gonzalez- Sanchez
Insulin Resistance and Glucose Allostasis - Prof. Michael Stumvoll
What data is available that shows insulin resistance as a... - Dr. Andrew P. Selwyn
Are Free Fatty Acids the Link between Obesity, Insulin... - Dr. Guenther Boden
Insulin Resistance and B-Cell Dysfunction: Changing the... - Dr. Samuel Dagogo-Jack
The Role of Increased Free Fatty Acids in the Metabolic... - Dr. Meredith Hawkins
Insulin resistance and the heart : A target for treatment ? - Dr. Lawrence Young
The brain : Off limits for the insulin resistance syndrome ? - Dr. Gareth Williams
Insulin resistance and hyperglycemia - Groups 1&2
Insulin resistance and CVD - Groups 3&4
Mechanisms of nutrient-mediated insulin resistance - Dr. Meredith Hawkins
Inflammation, insulin resistance and CHD - Prof. Steven M. Haffner
How does insulin regulate gene expression in health and... - Dr. Phillip Marsden
New roles for leptin and resistin - Dr. Ali Imran
Insulin Resistance and Disease Progression in Diabetes: An... - Dr. Ehud Ur
Insulin Resistance and Cardiovascular Disease - Role of the... - Dr. Subodh Verma
Insulin Resistance and the Endothelium - Clinical... - Dr. Peter Liu
The Insulin Resistance Syndrome and Cardiovascular Risk in... - Dr. Ivan G. Fantus
Insulin Resistance, Microalbuminuria and the Kidney - Dr. Sheldon Tobe
Managing Type 2 Diabetes: More than Sugar - Dr. Lawrence A. Leiter
Is Insulin Resistance A risk for Cardiovascular Disease?... - Dr. Amanda Adler
Role of abdominal fat distribution in determining insulin... - Prof. Steven Kahn
The Epidemic of Insulin Resistance and its Metabolic... - Prof. Bernard Zinman
Panel Discussion: Insulin Resistance Versus Insulin... - Dr. Stuart A Ross
Panel Discussion: Is Insulin Resistance a Risk for... - Prof. Bernard Zinman
Insulin Resistance Is A Risk Factor For Cardiovascular... - Dr. Ehud Ur
Insulin action: The key roles of insulin receptor kinase... - Dr. Barry Posner
Insulin Resistance and Islet Apoptosis - Prof. Daniel J. Drucker
Metabolic Complications of Insulin Resistance: Focus on... - Dr. Gary F. Lewis
Cellular mechanisms of insulin resistance: Implications for... - Dr. Gerald Shulman
Vascular Insulin Resistance: The Syndrome X Files - Dr. Ross Feldman
Beta Cell Apoptosis and Diabetes - Dr. Minna Woo
Panel discussion: Mechanisms of Insulin Resistance,... - Dr. Lawrence A. Leiter
Diabetes and CHD : Inflammation in Insulin Resistance... - Prof. Steven M. Haffner
Diabetes and CHD : Inflammation in Insulin Resistance... - Prof. Steven M. Haffner
Targeting Insulin Resistance in Type 2 Diabetes - Prof. Harold Lebovitz
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 Presentation 

"Adipocyte-Derived Factors: Effects on Insulin Sensitivity and Cardiovascular Disease"

Prof. Philipp Scherer (biography)
English - 2006-12-06 - 54 minutes
(48 slides)

Summary :
Adipocyte-derived factors are known to have an impact on various processes, including inflammation, angiogenesis, and energy homeostasis, among others.

Adiponectin is a well-studied adipocyte-derived factor shown to have potent anti-atherosclerotic properties, and a number of studies have looked at circulating adiponectin levels and the risk of future cardiovascular disease. High...

Learning objectives :
- Adipocyte-derived factors and their major physiological impact
- Appreciate the systemic contributions of adipose tissue to inflammation
- Understand the contribution of adiponectin towards glucose homeostasis
- Understand the epidemiological correlations between CVD and adiponectin

Bibliographic references :
1. Tobias Pischon, MD, MPH; Cynthia J. Girman, DrPH; Gokhan S. Hotamisligil, MD, PhD; Nader Rifai, PhD; Frank B. Hu, MD, PhD; Eric B. Rimm, ScD Plasma Adiponectin Levels and Risk of Myocardial Infarction in Men JAMA. 2004;291:1730-1737.

2. Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H, Imai Y, Nagai R, Kadowaki T.Measurement of the High–Molecular Weight Form of Adiponectin in Plasma Is Useful for the Prediction of Insulin Resistance and Metabolic Syndrome Diabetes Care. 2006;29:1357-1362.

3. Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C, Scherer PE, Hawkins M.Mechanisms of Early Insulin-Sensitizing Effects of Thiazolidinediones in Type 2 Diabetes Diabetes 53:1621-1629, 2004.

4. Kusminski CM, McTernan PG, Schraw T, Kos K, O'hare JP, Ahima R, Kumar S, Scherer
PE.Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution
from serum.
Diabetologia. 2007 Mar;50(3):634-42.

   


 Presentation 

"Insulin Resistance in Children and Adolescents with Type 1 Diabetes Mellitus: Relation to Obesity"

Dr. Thomas Reinehr (biography)
English - 2006-03-27 - 21 minutes
(18 slides)

Learning objectives :
After viewing this presentation, the participant will be able to discuss:

o The difficulties in determinating insulin resistance in obese type 1 diabetic children
o New models to calculate insulin resistance in obese type 1 diabetic children

   


 Presentation 

"Insulin Resistance and Cardiovascular Disease - Pleiotropic Effects of Glitazones"

Dr. Subodh Verma (biography)
English - 2005-11-08 - 70 minutes
(51 slides)
(35 slides)

Summary :
Insulin resistance is associated with increased cardiovascular risk even after adjusting for traditional and non-traditional risk factors (1), and in 2002 the American Heart Association stated that “Treating insulin resistance early should be part of a global cardiovascular and metabolic strategy.”

The syndrome of insulin resistance includes at least 20 different abnormalities...

Learning objectives :
After viewing this presentation the participant will be able to discuss:

- Evidence for the link between insulin resistance and CVD risk
- Direct and indirect pathways through which PPARγ can affect atherosclerosis
- Experimental and clinical evidence for pleiotropic vascular benefits of glitazones
- Ongoing outcome studies with glitazones

Bibliographic references :
1. Anthony J.G. Hanley, PhD, Ken Williams, MSc, Michael P. Stern, MD and Steven M. Haffner, MDHomeostasis Model Assessment of Insulin Resistance in Relation to the Incidence of Cardiovascular Disease: The San Antonio Heart StudyDiabetes Care 25:1177-1184, 2002.

   


 Presentation 

"Obesity and Insulin Resistance: Precursors for Type 2 Diabetes"

Prof. John Prins (biography)
English - 2005-09-11 - 35 minutes
(33 slides)
(3 questions)

Summary :
Obesity is commonly associated with a number of clinical features and /or pathologies that, collectively, have been termed the “metabolic syndrome”. Early definitions of the metabolic syndrome as proposed by Reaven and the World Health Organization regarded insulin resistance as the central and cardinal feature. More recent definitions from the National Cholesterol Education Program and the...

Learning objectives :
After viewing this presentation the participant will be able to discuss:

- How excess energy causes events contributing to type 2 diabetes
- The role of adipokines in obesity and metabolic syndrome: adiponectin

   


 Presentation 

"Insulin Resistance, Inflammation and Atherosclerosis in Type 2 Diabetes, and the Emerging Role of the Glitazones"

Prof. Nikolaus Marx (biography)
English - 2005-09-11 - 40 minutes
(43 slides)
(8 questions)

Summary :
Patients with type 2 diabetes mellitus and insulin resistance exhibit an increased propensity to develop arteriosclerosis with its sequelae of acute myocardial infarction and stroke. Developing therapeutic strategies to modulate the increased cardiovascular risk in these patients is one of the major tasks in vascular biology. Amongst such approaches, the antidiabetic, peroxisome...

Learning objectives :
After viewing this presentation the participant will be able to discuss:

- Evidence for effects of PPAR gamma activators on mechanisms of atherogenesis

Bibliographic references :
Donghoon Choi, MD, PHD, Soo-Kyung Kim, MD, Sung-Hee Choi, MD, Young-Guk Ko, MD, Chul-Woo Ahn, MD, PHD, Yangsoo Jang, MD, PHD, Sung-Kil Lim, MD, PHD, Hyun-Chul Lee, MD, PHD and Bong-Soo Cha, MD, PHDPreventative Effects of Rosiglitazone on Restenosis After Coronary Stent Implantation in Patients With Type 2 Diabetes Diabetes Care 27:2654-2660, 2004.

Steven M. Haffner, MD; Andrew S. Greenberg, MD; Wayde M. Weston, PhD; Hongzi Chen, PhD; Ken Williams, MS; Martin I. Freed, MD Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus Circulation. 2002;106:679.

Jürgen Hetzel; Bernd Balletshofer; Kilian Rittig; Daniel Walcher; Wolfgang Kratzer; Vinzenz Hombach; Hans-Ulrich Häring; Wolfgang Koenig; Nikolaus Marx Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1804.

Nikolaus Marx; Johannes Froehlich; Laila Siam; Jochen Ittner; Gerhard Wierse; Arnold Schmidt; Hubert Scharnagl; Vinzenz Hombach; Wolfgang Koenig Antidiabetic PPAR-Activator Rosiglitazone Reduces MMP-9 Serum Levels in Type 2 Diabetic Patients With Coronary Artery Disease Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:283.

Jagdip S. Sidhu; Zoltan Kaposzta; Hugh S. Markus; Juan Carlos Kaski Effect of Rosiglitazone on Common Carotid Intima-Media Thickness Progression in Coronary Artery Disease Patients Without Diabetes Mellitus Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:930.

   


 Presentation 

"Measuring Insulin in Clinical Practice"

Prof. David R. Matthews (biography)
English - 2005-06-10 - 36 minutes
(46 slides)

Summary :
In this presentation Prof. Matthews discusses some philosophical aspects about insulin resistance and ways in which it can be measured.

In the clinical setting, assessment of insulin resistance can be made without measurement, for example by looking at factors such as a person's weight or BMI, among others. There is a tendency to assume that insulin resistance is a defect or a...

Learning objectives :
After viewing this presentation the participant will be able to discuss:

- Measuring insulin resistance in clinical practice
- Concepts of IR
- Infusion methods clamps and steady state infusions
- Minimal models
- HOMA
- CVs
- Philosophy of IR as a physiological state not a pathological one

Bibliographic references :
R N Bergman, L S Phillips, and C Cobelli. Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose. J Clin Invest. 1981 December; 68(6): 1456–1467.

DeFronzo RA.Pathogenesis of glucose intolerance in uremia.Metabolism. 1978 Dec;27(12 Suppl 2):1866-80.

DC Shen, SM Shieh, MM Fuh, DA Wu, YD Chen and GM Reaven. Resistance to insulin-stimulated-glucose uptake in patients with hypertension JCEM.1988;66:580-583.

Turner RC, Holman RR, Matthews D, Hockaday TD, Peto J. Insulin deficiency and insulin resistance interaction in diabetes: estimation of their relative contribution by feedback analysis from basal plasma insulin and glucose concentrations. Metabolism. 1979 Nov;28(11):1086-96.

Tara M. Wallace, MD, Jonathan C. Levy, MD and David R. Matthews,
MD. Use and Abuse of HOMA Modeling Diabetes Care 27:1487-1495, 2004.

   


 Presentation 

"Polymorphism -308 G/A of the TNF-(alpha) Gene: Effect on plasma soluble TNF-receptor 2 (sTNFR2) according to Degree of Glucose Tolerance (IGT, DM2), Insulin Resistance (IR), and other Related Parameters. A Population Based Study (The Segovia Study, Spain)"

Dr. Jose Luis Gonzalez- Sanchez (biography)
English - 2005-04-14 - 14 minutes
(16 slides)

Summary :
To investigate the relationships between the -308 G/A TNF-(alpha) polymorphism on plasma sTNFR2 levels, IR and other related parameters 436 unrelated subjects (49.1% males; 35-74 years) from a cross-sectional population-based survey in the province of Segovia (Spain) were studied.

Measurements: BMI, waist circumference (WC), sagittal abdominal diameter (SAD), systolic and...

Learning objectives :
After viewing this presentation the participant will be able to discuss:

Data from the population based Segovia study on the relationship between the -308 G/A polymorphism of the TNF-alpha gene, and the following:

- Plasma soluble TNF-alpha receptor 2 in DM2
- Insulin resistance
- Other related parameters

   


 Presentation 

"Insulin Resistance and Glucose Allostasis"

Prof. Michael Stumvoll (biography)
English - 2005-04-14 - 34 minutes
(28 slides)

Summary :
Maintance of glycemia is of vital importance. Regulation of glycemia is accomplished by the balanced interplay between insulin action and insulin secretion. It is common belief that in healthy humans plasma glucose concentration is regulated by a homeostatic system, i.e. a system designed to maintain plasma glucose concentration constant. Here we review evidence that in response to a chronic...

Learning objectives :
After viewing this presentation, participants will be able to discuss:
• The variation of serum glucose levels with different degrees of insulin resistance (IR)
• The signals that may be responsible for the increase beta cell response to IR
• The definition of the Disposition Index (DI)
• The definition of the Beta Cell Demand Index (BCDI)
• The relationship of both the DI and the BCDI to serum glucose levels

Bibliographic references :
Michael Stumvoll, P. Antonio Tataranni, Norbert Stefan, Barbora Vozarova, and Clifton Bogardus Glucose Allostasis Diabetes 52:903-909, 2003

Stumvoll M, Tataranni PA, Bogardus C. The hyperbolic law--a 25-year perspective. Diabetologia. 2005 Feb;48(2):207-9.

Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005 Apr;365(9467):1333-46.

Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest. 1999 Sep;104(6):787-94.

Goran MI, Gower BA. Longitudinal study on pubertal insulin resistance. Diabetes. 2001 Nov;50(11):2444-50

   


 Presentation 

"What data is available that shows insulin resistance as a risk factor of CVD? How compelling is it?"

Dr. Andrew P. Selwyn (biography)
English - 2004-06-04 - 12 minutes
(4 slides)

Summary :
Insulin resistance and atherosclerosis often appear together. Insulin resistance in these patients can be detected not only by sophisticated tests but by some simple observations of hypertension, hyperglycaemia and dyslipidemia involving small dense low-density lipoprotein (sdLDL) particles.

These patients also have slightly decreased high-density lipoprotein (HDL) levels, impaired...

Learning objectives :
After viewing these slides the particpant will be able to discuss:

- Clinical indicators of insulin resistance in patients with atherosclerosis

- Data from prospective studies showing:
-->the relationship of insulin resistance to CVD risk
-->the incidence of IGT and new onset diabetes in patients with MI

Bibliographic references :
Anthony J.G. Hanley, PhD, Ken Williams, MSc, Michael P. Stern, MD and Steven M. Haffner, MD.Homeostasis Model Assessment of Insulin Resistance in Relation to the Incidence of Cardiovascular Disease Diabetes Care 2002;25:1177-1184.

Anna Norhammar, Åke Tenerz, Göran Nilsson, Anders Hamsten, Suad Efendíc, Lars Rydén and Klas Malmberg.Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study The Lancet 2002;359(9324):2140-2144.

   


 Presentation 

"Are Free Fatty Acids the Link between Obesity, Insulin Resistance, Endothelial Dysfunction and Atherosclerosis?"

Dr. Guenther Boden (biography)
English - 2003-08-28 - 49 minutes
(31 slides)
(1 question)

Summary :
Recorded during the 18th IDF Meeting, Paris: We are now learning more about the role of elevated FFAs in insulin resistance. Fatty acids are necessary within the muscle cell to an extent, as a source of fuel for the mitochondria, but elevated fatty acids can cause insulin resistance as we will see here. When fatty acids enter the cell, they get activated to long form Acyl-CoA and then esterified...

Learning objectives :
The participant will learn the mechanism whereby plasma FFAs enter the muscle cell and cause insulin resistance, and how this affects the development of atherosclerosis, inflammation and endothelial dysfunction.

Bibliographic references :
Boden G.Effects of Free Fatty Acids (FFA) on Glucose Metabolism: Significance for Insulin Resistance and Type 2 Diabetes.

Boden G, Cheung P, Mozzoli M, Fried SK.Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes.

   


 Presentation 

"Insulin Resistance and B-Cell Dysfunction: Changing the Consequences of the Disease Continuum"

Dr. Samuel Dagogo-Jack (biography)
English - 2003-06-16 - 34 minutes
(21 slides)

Summary :
The prediabetic state is characterized by IFG or IGT, but we have more information about IGT since its use in the large clinical trials, and it is not clear whether they predict the same outcomes. It was recently shown that individuals with IFG were as insulin resistant as those with established type 2 diabetes, and beta cell function was elevated. (Dagogo-Jack S et al. Diabetes. 2003; 52: (suppl...

Learning objectives :
The participant will learn new information about IFG, and the role of PPAR gamma agonists in improving beta cell function:

- IFG individuals were found to be as insulin resistant as those with type 2 diabetes, and had elevated beta cell function (Dagogo-Jack S et al. Diabetes. 2003; 52: (suppl 1):A285.

- Rosiglitazone improves beta cell function in monotherapy and in combination (Data on file, GlaxoSmithKline).

Bibliographic references :
Corbett JA, McDaniel ML. Intraislet release of interleukin 1 inhibits beta cell function by inducing beta cell expression of inducible nitric oxide synthase. J Exp Med. 1995 Feb 1;181(2):559-68.

   


 Presentation 

"The Role of Increased Free Fatty Acids in the Metabolic Derangement’s of Type 2 DM"

Dr. Meredith Hawkins (biography)
English - 2003-05-23 - 50 minutes
(30 slides)
(7 questions)

Summary :
The role of circulating free fatty acids (FFAs) in insulin resistance is many-fold, as it affects the major organs controlling glucose metabolism and homeostasis: increased levels of FFAs cause impaired insulin secretion from the pancreas, diminished glucose uptake in skeletal muscle and inappropriate levels of glucose output from the liver. Just how much does this increased hepatic glucose...

Learning objectives :
The participant will review some new data from Dr M Hawkins and colleagues which provide insights into:

- the mechanism whereby increased FFAs affect hyperglycemia in type 2 DM
- the relationship between FFA and PAI-1 levels
- the importance of increased plasma adiponectin levels arising in TZD therapy


- Chronic increases in FFA availability contribute substantially to the loss of regulation of glucose production by hyperglycemia per se in DM2.

- Lowering plasma FFA levels in DM2 is potentially of therapeutic benefit in restoring normal effectiveness of glucose to regulate hepatic glucose fluxes.

- It has been demonstrated for the first time in humans that increased circulating FFA levels can contribute substantially to the inappropriately elevated plasma PAI-1 levels seen in type 2 diabetes mellitus and thus in turn to the prothrombic state.

- Given the time course and magnitude of effect, it is likely that increases in plasma levels of the fat-derived peptide adiponectin may contribute importantly to the beneficial effects of thiazolidinediones on insulin action in people with type 2 diabetes mellitus.

Bibliographic references :
Lam TK, Carpentier A, Lewis GF, van de Werve G, Fantus IG, Giacca A. 2003.Mechanisms of the free fatty acid-induced increase in hepatic glucose production. Am J Physiol Endocrinol Metab 284(5):E863-73.

   


 Presentation 

"Insulin resistance and the heart : A target for treatment ?"

Dr. Lawrence Young (biography)
English - 2003-03-29 - 46 minutes
(38 slides)
(5 questions)

Summary :
A high rate of myocardial metabolism is needed to generate energy in order to sustain cardiac contractile activity. Typically, energy generation occurs through the metabolism of free fatty acids, glucose, and lactate. However, in insulin-resistance and diabetic individuals, excessive free fatty acid metabolism occurs in the heart. Pharmacologic manipulation of myocardial metabolism may be...

Learning objectives :
The potential beneficial effects of the TZDs on myocardial glucose and free fatty acid metabolism.

Bibliographic references :
J Cardiovasc Pharmacol Ther 2002 Oct;7(4):207-10 Thiazolidinediones Could Improve Endothelial Dysfunction and Risk of Premature Coronary Heart Disease in HIV-Infected Patients.

Carrillo-Jimenez R, Lamas GA, Hennekens CH.

--------------------------------------------------------------------------

Circulation 2003 Mar 18;107(10):1448-53
Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism).

Steinberger J, Daniels SR; American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism).

Full text article at :

http://circ.ahajournals.org/cgi/content/full/107/10/1448

   


 Presentation 

"The brain : Off limits for the insulin resistance syndrome ?"

Dr. Gareth Williams (biography)
English - 2003-03-29 - 50 minutes
(27 slides)
(6 questions)

Summary :
It is generally assumed that the brain functions largely independently of insulin. However, it has become clear that insulin can enter the brain from the circulation, and acts on defined neuronal pathways to influence important metabolic activities including food intake and sympathetic outflow to various organs. Blunting of specific central actions of insulin have been demonstrated in various...

Learning objectives :
- The action of insulin in brain-regulated metabolic activities
- The understanding of certain TZD effects linked to insulin sensitivity

Bibliographic references :
J Neuroendocrinol 2003 Jan;15(1):75-9
Cerebral insulin increases brain response to glucose.

Alquier T, Leloup C, Atef N, Fioramonti X, Lorsignol A, Penicaud L.

   


 Presentation 

"Insulin resistance and hyperglycemia"

Groups 1&2 (biography)
English - 2003-03-29 - 22 minutes
(14 slides)

Summary :
Group 1: The purpose of this workshop was to speculate on whether current agents accelerate B cell loss, and how this may affect current practice. We know that when diabetes occurs, beta cell failure is well advanced, but it’s not clear whether early disease with limited failure is more responsive to IR reduction or beta cell failure reduction. The current clinical opinion and behaviour in this...

Learning objectives :
The participant will learn what are the current consensuses among physicians regarding the treatment of IR:
- Preliminary studies indicate that TZDs may have a greater preventative role in early disease rather than only in late disease
- IR for the purpose of this discussion is a clinical syndrome of impaired insulin action which could be different in different tissues
- We can implement better treatment of IR in several ways, including having Metabolic Syndrome clinics, working with pediatric groups, and getting help in promoting lifestyle.


Bibliographic references :
Effects of insulin resistance and insulin secretion on the efficacy of interventions to retard development of type 2 diabetes mellitus: the DA Qing IGT and Diabetes Study.

Li G, Hu Y, Yang W, Jiang Y, Wang J, Xiao J, Hu Z, Pan X, Howard BV, Bennett PH.

Department of Endocrinology, China-Japan Friendship Hospital, Yinghua Yeast Street, Caoyang District, 100029, Beijing, People's Republic of China

OBJECTIVE: To investigate the effects of insulin resistance (IR) and insulin secretion (IS) on the development of diabetes mellitus in individuals with impaired glucose tolerance (IGT) who underwent lifestyle interventions. METHODS: 284 out of 577 individuals with IGT identified by population-based screening in Da Qing, China, who were randomized to undergo diet change and/or increased physical activity had baseline fasting and 2 h post-load insulin determinations. They were followed for 6 years for the development of diabetes. IR and IS were assessed using calculated indices based on fasting plasma insulin and glucose. The interactions of IR, IS, obesity and plasma glucose and the effects of the lifestyle interventions were evaluated using Cox Proportional Hazards analysis. RESULTS: Both IR and IS were significantly associated with the development of diabetes. Lifestyle interventions were more effective in those with lower IT and higher IS at baselin. Diet plus exercise interventions resulted in significantly lower incidence of diabetes, even after controlling for IR, IS, BMI and 2hrPG. CONCLUSION: Both IR and beta-cell function were predictors of diabetes in Chinese with IGT. Lifestyle intervention reduced the incidence of DM and these interventions were more effective in those with less IR.

Diabetes Res Clin Pract 2002 Dec;58(3):193-200


   


 Presentation 

"Insulin resistance and CVD"

Groups 3&4 (biography)
English - 2003-03-29 - 22 minutes
(14 slides)

Summary :
Group 3: The purpose of this workshop was to assess the data supporting IR as the cause of atherosclerosis, and determine if and/or when an IR treatment strategy can be used to manage metabolic syndrome. There is epidemiological data suggesting a link between IR and atherosclerosis, and carotid IMT evidence of improvement of atherosclerosis with insulin sensitizers. So should we be using TZDs in...

Learning objectives :
The participant will gain an understanding of the current state of decision making on prescribing insulin sensitizers to reduce cardiovascular events in type 2 diabetics:
- There is a need to further evaluate current therapy
- Outcome studies are needed to clarify whether treating IR does in fact decrease cardiovascular events


Bibliographic references :
Association between insulin resistance and carotid arteriosclerosis in subjects with normal fasting glucose and normal glucose tolerance.

Ishizaka N, Ishizaka Y, Takahashi E, Unuma T, Tooda E, Nagai R, Togo M, Tsukamoto K, Hashimoto H, Yamakado M.

Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, Japan. nobuishizka-tky@umin.ac.jp

OBJECTIVE: We examined the possible association between insulin resistance and carotid arteriosclerosis in subjects who had both normal fasting glucose and normal glucose tolerance after intake of a glucose load. METHODS AND RESULTS: Our subjects were individuals who underwent general health screening at our institute, which included carotid ultrasound and oral glucose tolerance testing. Of the 1238 subjects enrolled in our study, 738 (60%) were classified as normal, defined as a normal fasting glucose level and normal glucose tolerance, and 334 (27%) and 166 (13%) were classified as borderline and diabetic, respectively, according to the criteria of the Japan Diabetes Society. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to measure insulin resistance. In normal-type subjects, univariate analysis showed that insulin resistance, but not insulin secretion, was associated with the presence of carotid plaque. Multivariate analysis showed that HOMA-IR was positively associated with carotid plaque in normal-type subjects, with an odds ratio of 1.19 (95% confidence interval, 1.00 to 1.41; P<0.05). CONCLUSIONS: These data suggest the possibility that the presence of higher insulin resistance could be a risk factor for carotid arteriosclerosis in subjects with normal fasting glucose and normal glucose tolerance.

Arterioscler Thromb Vasc Biol 2003 Feb 1;23(2):295-301




   


 Presentation 

"Mechanisms of nutrient-mediated insulin resistance"

Dr. Meredith Hawkins (biography)
English - 2003-03-28 - 60 minutes
(34 slides)
(14 questions)

Summary :
Obesity plays a central role in the pathogenesis of the insulin resistance syndrome, which in turn confers a heightened risk of diabetes mellitus and atherosclerosis. Besides the health consequences of the increased fat mass per se, excess nutrient availability in obesity also appears to contribute to this syndrome. The nutrient excess refers to increased oral intake and circulating levels of...

Learning objectives :
The pathogenesis of obesity in the insulin resistance syndrome : the role of high plasma FFA levels on metabolism and adipocyte-derived proteins.

Bibliographic references :
Ann N Y Acad Sci 2002 Jun;967:283-98
Fatty acid regulation of gene expression: a genomic explanation for the benefits of the mediterranean diet.

Clarke SD, Gasperikova D, Nelson C, Lapillonne A, Heird WC.

Institute for Cellular and Molecular Biology and Division of Nutritional Sciences, University of Texas, Austin 78712, USA. stevedclarke@mail.utexas.edu

The development of obesity and associated insulin resistance involves a multitude of gene products, including proteins involved in lipid synthesis and oxidation, thermogenesis, and cell differentiation. The genes encoding these proteins are in essence the blueprints that we have inherited from our parents. However, what determines the way in which blueprints are interpreted is largely dictated by a collection of environmental factors. The nutrients we consume are among the most influential of these environmental factors. During the early stages of evolutionary development, nutrients functioned as primitive hormonal signals that allowed the early organisms to turn on pathways of synthesis or storage during periods of nutrient deprivation or excess. As single-cell organisms evolved into complex life forms, nutrients continued to be environmental factors that interacted with hormonal signals to govern the expression of genes encoding proteins involved in energy metabolism, cell differentiation, and cell growth. Nutrients govern the tissue content and activity of different proteins by functioning as regulators of gene transcription, nuclear RNA processing, mRNA degradation, and mRNA translation, as well as functioning as posttranslational modifiers of proteins. One dietary constituent that has a strong influence on cell differentiation, growth, and metabolism is fat. The fatty acid component of dietary lipid not only influences hormonal signaling events by modifying membrane lipid composition, but fatty acids have a very strong direct influence on the molecular events that govern gene expression. In this review, we discuss the influence that (n-9), (n-6), and (n-3) fatty acids exert on gene expression in the liver and skeletal muscle and the impact this has on intra- and interorgan partitioning of metabolic fuels.

J Clin Invest 1997 May 1;99(9):2173-82
Role of the glucosamine pathway in fat-induced insulin resistance.

Hawkins M, Barzilai N, Liu R, Hu M, Chen W, Rossetti L.

Division of Endocrinology and Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

To examine whether the hexosamine biosynthetic pathway might play a role in fat-induced insulin resistance, we monitored the effects of prolonged elevations in FFA availability both on skeletal muscle levels of UDP-N-acetyl-hexosamines and on peripheral glucose disposal during 7-h euglycemic-hyperinsulinemic (approximately 500 microU/ml) clamp studies. When the insulin-induced decrease in the plasma FFA levels (to approximately 0.3 mM) was prevented by infusion of a lipid emulsion in 15 conscious rats (plasma FFA approximately 1.4 mM), glucose uptake (5-7 h = 32.5+/-1.7 vs 0-2 h = 45.2+/-2.8 mg/kg per min; P < 0.01) and glycogen synthesis (P < 0.01) were markedly decreased. During lipid infusion, muscle UDP-N-acetyl-glucosamine (UDP-GlcNAc) increased by twofold (to 53.4+/-1.1 at 3 h and to 55.5+/-1.1 nmol/gram at 7 h vs 20.4+/-1.7 at 0 h, P < 0.01) while glucose-6-phosphate (Glc-6-P) levels were increased at 3 h (475+/-49 nmol/gram) and decreased at 7 h (133+/-7 vs 337+/-28 nmol/gram at 0 h, P < 0.01). To discern whether such an increase in the skeletal muscle UDP-GlcNAc concentration could account for the development of insulin resistance, we generated similar increases in muscle UDP-GlcNAc using three alternate experimental approaches. Euglycemic clamps were performed after prolonged hyperglycemia (18 mM, n = 10), or increased availability of either glucosamine (3 micromol/kg per min; n = 10) or uridine (30 micromol/kg per min; n = 4). These conditions all resulted in very similar increases in the skeletal muscle UDP-GlcNAc (to approximately 55 nmol/gram) and markedly impaired glucose uptake and glycogen synthesis. Thus, fat-induced insulin resistance is associated with: (a) decreased skeletal muscle Glc-6-P levels indicating defective transport/phosphorylation of glucose; (b) marked accumulation of the endproducts of the hexosamine biosynthetic pathway preceding the onset of insulin resistance. Most important, the same degree of insulin resistance can be reproduced in the absence of increased FFA availability by a similar increase in skeletal muscle UDP-N-acetyl-hexosamines. In conclusion, our results support the hypothesis that increased FFA availability induces skeletal muscle insulin resistance by increasing the flux of fructose-6-phosphate into the hexosamine pathway.


Diabetes 2001 Feb;50(2):418-24
Free fatty acids induce peripheral insulin resistance without increasing muscle hexosamine pathway product levels in rats.

Choi CS, Lee FN, Youn JH.

Diabetes Research Center, Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles 90089-9142, USA.

To evaluate the role of the hexosamine biosynthesis pathway (HBP) in fat-induced insulin resistance, we examined whether fat-induced insulin resistance is additive to that induced by increased HBP flux via glucosamine infusion and, if so, whether such additive effects correlate with muscle HBP product levels. Prolonged hyperinsulinemic (approximately 550 pmol/l) euglycemic clamps were conducted in conscious overnight-fasted rats. After the initial 150 min to attain steady-state insulin action, rats received an additional infusion of saline, Intralipid, glucosamine, or Intralipid and glucosamine (n = 8 or 9 for each) for 330 min. At the conclusion of clamps, skeletal muscles (soleus, extensor digitorum longus, and tibialis anterior) were taken for the measurement of HBP product levels. Intralipid and glucosamine infusions decreased insulin-stimulated glucose uptake (Rd) by 38 and 28%, respectively. When the infusions were combined, insulin-stimulated Rd decreased 47%, significantly more than with Intralipid or glucosamine alone (P < 0.05). The glucosamine-induced insulin resistance was associated with four- to fivefold increases in muscle HBP product levels. In contrast, the Intralipid-induced insulin resistance was accompanied by absolutely no increase in HBP product levels in all of the muscles examined. Also, when infused with glucosamine, Intralipid decreased insulin action below that with glucosamine alone without changing HBP product levels. In a separate study, short-term (50 and 180 min) Intralipid infusion also failed to increase muscle HBP product levels. In conclusion, increased availability of plasma free fatty acids induces peripheral insulin resistance without increasing HBP product levels in skeletal muscle.

   


 Presentation 

"Inflammation, insulin resistance and CHD"

Prof. Steven M. Haffner (biography)
English - 2003-03-28 - 69 minutes
(41 slides)
(4 questions)

Summary :
Type 2 diabetes is associated with a marked increase in coronary heart disease; however, the severity of glycemia during the diabetic phase is only modestly related to the risk of coronary heart disease. Because of this observation, most interest is focused on the pre-diabetic state. Many studies have shown increased cardiovascular risk factors prior to the onset of type 2 diabetes. In the San...

Learning objectives :
- The effect of insulin resistance on coronary heart disease in the pre-type 2 diabetic state
- The interrelationships between the risk of CHD, CRP levels, insulin resistance and metabolic syndrome
- The influence of rosiglitazone and insulin sensitizers on CRP levels

   


 Presentation 

"How does insulin regulate gene expression in health and disease ?"

Dr. Phillip Marsden (biography)
English - 2003-03-28 - 44 minutes
(33 slides)
(1 question)

Summary :
Newer insights are emerging with respect to how insulin, the key anabolic hormone, modulates gene expression in health. Insulin controls the amount of key proteins through actions that affect steady-state levels of mRNA, through direct effects on transcription of the gene or indirectly through effects on genral modifiers of transcription. Perturbations in the processes that mediate...

Learning objectives :
Importantly, insulin controls the amount of key proteins by modifying the efficiency of mRNA translation. This review provides examples of the relevance of the insulin-induced changes in the mRNA translational process in health and disease.

Bibliographic references :
http://www.pubmedcentral.gov/articlerender.fcgi?tool=pubmed&pubmedid=12618528

J Clin Invest 2003 Mar;111(5):737-47
Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes.

Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B Jr, Reitman ML, Gonzalez FJ.

   


 Presentation 

"New roles for leptin and resistin"

Dr. Ali Imran (biography)
English - 2003-03-28 - 19 minutes
(17 slides)

Summary :
Leptin and resistin are two members of a growing family of adipocytokines. Leptin is thought to regulate body fat, feeding behaviour, energy balance, fertility and neuroendocrine responses; whereas resistin antagonizes insulin action, impairs glucose tolerance and its activity is modulated by PPAR gamma receptors. It was previously shown that leptin is expressed in the rat hypothalamus and...

Learning objectives :
The participant will acquire new knowledge about the regulation and expression patterns of leptin and resistin:

- Leptin mRNA, protein and receptors are developmentally regulated in the pituitary.
- Leptin receptors and protein are both expressed in the hypothalamus and pituitary, and are independently regulated.
- Resistin is expressed in the mouse brain and pituitary, along with PPAR – gamma receptors.
- Pituitary resistin is also developmentally regulated.
- Pituitary resistin expression is dependent upon an intact hypothalamus.


Bibliographic references :
Morash BA, Willkinson D, Ur E, Wilkinson M. 2002. Resistin expression and regulation in mouse pituitary. FEBS Lett. Aug 28;526(1-3):26-30
http://www.ncbi.nlm.nih.gov/entrez

Morash B, Wilkinson D, Murphy P, Ur E, Wilkinson M. 2001. Developmental regulation of leptin gene expression in rat brain and pituitary. Mol Cell Endocrinol. Dec 20;185(1-2):151-9
http://www.ncbi.nlm.nih.gov/entrez

   


 Presentation 

"Insulin Resistance and Disease Progression in Diabetes: An Endocrine Perspective"

Dr. Ehud Ur (biography)
English - 2002-11-23 - 45 minutes
(45 slides)

Summary :
It is estimated that by the year 2020 there will be approximately 250 million people affected by Type 2 diabetes (DM2) worldwide. In Canada, the current prevalence is expected to double by that date.
Although the underlying cause of diabetes is unknown, it is clear that insulin resistance (IR) plays a major role in the development and progression of the disease. Progressively worsening...

Learning objectives :
The participant will gain some new insights into diabetes progression and treatment:

- Treatment gaps in diabetes would be helped by targeting microvascular and macrovascular complications
- Our knowledge of the progression of diabetes is evolving and now includes the role of insulin resistance
- Several clinical trials are now underway to study diabetes prevention


Bibliographic references :
Almind K, Kulkarni RN, Lannon SM, Kahn CR. 2003. Identification of interactive Loci linked to insulin and leptin in mice with genetic insulin resistance. Diabetes 52(6):1535-43.
http://www.ncbi.nlm.nih.gov/entrez

   


 Presentation 

"Insulin Resistance and Cardiovascular Disease - Role of the Endothelium"

Dr. Subodh Verma (biography)
English - 2002-11-23 - 47 minutes
(36 slides)
(27 slides)

Summary :
The link between diabetes and cardiovascular disease is of special interest to all cardiologists. An emerging concept is that endothelial dysfunction, high C-reactive protein and inflammation may actually be the mechanistic basis for the link between diabetes and cardiovascular disease. The American Heart Association is recognizing the growing problem of the metabolic syndrome and how it is a...

Learning objectives :
The participant will learn how insulin resistance leads to endothelial dysfunction, a precursor for CVD; and also why C-reactive protein can be used to predict CVD:

- The endothelium releases various factors, one of which, NO, is implicated in heart disease. Others are angiotensin and endothelin-1, and insulin resistant patients produce less NO and more angiotensin and endothelin-1. They also overexpress the AII receptor, and ACE.

- Insulin plays a role in vasodilatation by stimulating NO release, which increases glucose uptake. Not only does an insulin resistant person have impaired glucose, fat and protein metabolism, but also resistance to the effects of insulin to stimulate release of NO.

- The vascular insulin resistance resulting in decreased production of NO decreases blood flow to skeletal muscle and accounts for about 25% of whole body insulin resistance. Treatment of vascular insulin resistance by ACE inhibitors may thus have a role in preventing new onset diabetes.

- New data suggest that insulin sensitizers improve endothelial function and are pleiotropic anti-atherosclerotic, anti-inflammatory drugs.

- Insulin resistance also promotes atherosclerosis and impaired vascular function through impaired fibrinolysis, due to excess PAI-1 levels. PAI-1 levels were shown to be lowered by Rosiglitazone (McGill JB et al. Diabetes. 1994; 43: 104-109).

- Insulin resistance may independently elevate BP, and hence insulin sensitizers may lower BP.

- Microalbuminuria is linked to IR, and albumin excretion is reduced by Rosiglitazone.

- Insulin resistance causes increased ACE and AII receptor expression, and Rosiglitazone reduces vascular ACE content.

- Insulin resistant patients have higher levels of CRP.

- Low levels of CRP quench NO in the endothelium, and stimulate endothelin-1 and IL-6 (Verma et al. Circulation. 2002). Rosiglitazone reduces CRP levels and CRP –induced endothelial dysfunction.

- Patients with metabolic syndrome have more vulnerable plaques, i.e., plaques more vulnerable to rupture.


Bibliographic references :
Verma S. 2002. Endothelin Antagonism and Insulin's Vascular Effects. Hypertension. Dec;40(6):e12-3
http://www.ncbi.nlm.nih.gov/entrez

Verma S, Arikawa E, Lee S, Dumont AS, Yao L, McNeill JH. 2002. Exaggerated coronary reactivity to endothelin-1 in diabetes: reversal with bosentan. Can J Physiol Pharmacol; Oct;80(10):980-6.
http://www.ncbi.nlm.nih.gov/entrez

   


 Presentation 

"Insulin Resistance and the Endothelium - Clinical Manifestations"

Dr. Peter Liu (biography)
English - 2002-11-16 - 33 minutes
(33 slides)

Summary :
Here we will try to shed some light on the relationship between insulin resistance and the cardiovascular disease that we see as a consequence of the process. A current concept is that of endothelial dysfunction: risk factors such as smoking, hypercholesterolemia and diabetes adversely affect the functioning of the endothelium, which leads to buildup of atherosclerotic plaque, plaque rupture and...

Learning objectives :
The participant will learn about the underlying mechanisms whereby insulin resistance is associated with endothelial dysfunction leading to CAD:

- Insulin resistance associated with endothelial dysfunction leads to CAD via metabolic stress, oxidative stress and inflammation.
- The key to therapy is to correct underlying factors causing insulin resistance by:
o Exercise and weightloss
o Using agents such as TZDs which not only treat insulin resistance but also decrease inflammatory markers and LDL oxidation, and improve endothelial function


Bibliographic references :
Blake GJ, Ridker PM. 2003. C-reactive protein and other inflammatory risk markers in acute coronary syndromes. J Am Coll Cardiol 2003 Feb 19;41(4 Suppl S):S37-42
http://www.ncbi.nlm.nih.gov


   


 Presentation 

"The Insulin Resistance Syndrome and Cardiovascular Risk in Type 2 Diabetic Patients: Pathophysiology and Implications for Assessment and Management"

Dr. Ivan G. Fantus (biography)
English - 2002-11-16 - 55 minutes
(32 slides)
(44 slides)

Summary :
The increasing prevalence of diabetes around the world is now well documented. This is due almost entirely to Type 2 diabetes and is most dramatic in developping nations. It appears to result, at least in part, from dramatic changes in lifestyle comprising Westernization of diet and decreased physical activity. These changes are associated with the development of obesity and insulin resistance,...

Learning objectives :
The participant will learn about the causes and actual and potential treatments of insulin resistance:

- The term “Metabolic Syndrome” has been adopted by the World Health Organization to describe the clinical phenotype comprising obesity and insulin resistance often accompanied by by other cardiovascular risk factors, e.g., hypertension, dyslipidemia, microalbuminuria.

- The central pathophysiologic abnormality of the Metabolic Syndrome is insulin resistance.

- In addition to susceptibility genes there are environmental factors which contribute to insulin resistance, as well as circulating factors such as hormones, high levels of insulin, adipocytokines, FFAs, glucose and amino acids.

- Inhibition of insulin resistance-inducing circulating factors and/or intracellular signaling molecules or conversely, enhancing those which increase insulin sensitivity is a major focus of the pharmaceutical industry.

- Physicians need to focus on the environmental contribution to the development of insulin resistance and type 2 diabetes, i.e., modifiable lifestyle.


Bibliographic references :
1. Zimmet P, Alberti KGMM, Shaw J, Global and societal implications of the diabtes epidemic. Nature 2001; 4145:782-7
2. Virkamaki A, Ueki K, Kahn CR. Protein-protien interaction in insulin signaling and the molecular mechanisms of insulin reistance. J. Clin Invest 1999; 103:931-43
3. Shepherd PR, Kahn BB. Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus. N Engl J Med 1999; 341:248-57.


   


 Presentation 

"Insulin Resistance, Microalbuminuria and the Kidney"

Dr. Sheldon Tobe (biography)
English - 2002-11-16 - 27 minutes
(31 slides)

Summary :
Microalbuminuria (MAU) refers to the presence of abnormally elevated amounts of albumin in the urine, at a level that cannot be detected by a urine dipstick. Because higher levels of blood pressure are consistenly linked to higher risk for ESRD1, blood pressure control is a natural step toward the goal of reducing the progression of kidney disease in the setting of diabetes.2 The use of...

Bibliographic references :
1. Lievre M, Marre M, Chatellier G, Plouin P, Reglier J, Richardson L et al. The non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and rampiril (DIABHYCAR) study : design, organization, and patients recruitment. DIABHYCAR Study Group. Controlled Clinical Trials 2000; 21: 383-96.
2. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators [see comments]. Lancet 2000;355:253-9
3. Andersen S, Blouch K, Bialek J, Deckert M, Parving HH, Myers BD. Glomerular permselectivity in early stages of overt diabetic nephropathy. Kidney International 2000;58: 2129-37
4. Lemley KV, Abdullah I, Myers BD, Meyer TW, Blouch K, Smith WE et al. Evolution of incipient nephropathy in type 2 diabetes mellitus. Kidney International 2000;58:1228-37.
5. Parving HH, Lenher H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P et al The effect of irbesartan on the development of diabetic nephropathy in patients with Type 2 diabetes. [see comments]. New England Journal of Medicine 2001;345:870-8.


   


 Presentation 

"Managing Type 2 Diabetes: More than Sugar"

Dr. Lawrence A. Leiter (biography)
English - 2002-11-16 - 33 minutes
(48 slides)

Summary :
Cardiovascular disease accounts for about 80% of deaths in individuals with diabetes. There is no doubt that this increased atherosclerosis is a result of multiple factors. Studies such as the DCCT in individuals with TYPE 1 diabetes and the UKPDS in persons with Type 2 Diabetes have shown that improved glycemic control clearly reduces the risk for microvascular complications. In neither study,...

   


 Presentation 

"Is Insulin Resistance A risk for Cardiovascular Disease? ''No''"

Dr. Amanda Adler (biography)
English - 2002-04-27 - 35 minutes
(51 slides)

Summary :
The many-fold increased risk of cardiovascular disease in diabetes results in cardiovascular disease being the most common complication in type 2 diabetes and the number one cause of death. Because of the association of type 2 diabetes with insulin resistance, it is logical to assess the association between insulin resistance per se and cardiovascular disease. Yet, insulin resistance appears to...

Learning objectives :
Insights into why insulin resistance syndrome, and not insulin resistance per se, is a risk for CVD.

Bibliographic references :
Epidemiology of the metabolic syndrome, 2002.

Meigs JB.

Harvard Medical School, General Medical Division, Massachusetts General Hospital, Boston, USA.

BACKGROUND: The close association of type 2 diabetes and atherosclerotic cardiovascular disease (CVD) suggests that they share a common physiologic antecedent, postulated to be tissue resistance to insulin. Insulin resistance is associated with a cluster of risk factors recognized as the metabolic syndrome. OBJECTIVE: To describe the epidemiology of the insulin resistance syndrome, also known as the metabolic syndrome.
METHODS: Overall obesity, central obesity, dyslipidemia characterized by elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol, hyperglycemia, and hypertension are common traits that, when they occur together, constitute the metabolic syndrome. The World Health Organization and the National Cholesterol Education Program Adult Treatment Panel III have proposed working definitions for the syndrome based on these traits. Cross-sectional and longitudinal epidemiologic studies provide an emerging picture of the prevalence and outcomes of the syndrome.
RESULTS: National survey data suggest the metabolic syndrome is very common, affecting about 24% of US adults who are 20 to 70 years of age and older. The syndrome is more common in older people and in Mexican Americans. People with the syndrome are about twice as likely to develop CVD and over 4 times as likely to develop type 2 diabetes compared with subjects who do not have metabolic syndrome. While this syndrome may have a genetic basis, environmental factors are important modifiable risk factors for the condition. CONCLUSIONS: The metabolic syndrome is very common and will become even more common as populations age and become more obese. Treatment for component traits is known to reduce the risk for type 2 diabetes and CVD; whether risk is reduced by treatment of the syndrome, specifically, remains uncertain. Primary care physicians must recognize that the co-occurrence of risk factors for type 2 diabetes and CVD represents an extremely adverse metabolic state warranting aggressive risk factor intervention.

Am J Manag Care 2002 Sep;8(11 Suppl):S283-92; quiz S293-6

   


 Presentation 

"Role of abdominal fat distribution in determining insulin sensitivity and other features of the metabolic syndrome"

Prof. Steven Kahn (biography)
English - 2002-04-27 - 35 minutes
(52 slides)

Summary :
It is well recognized that insulin resistance is a feature of a number of conditions and forms a basis for the metabolic syndrome, sometimes referred to as the insulin resistance syndrome. Obesity is also associated with insulin resistance as well as a number of other features of the metabolic syndrome. The relationship of body size and a number of measures of abdominal fat distribution with...

Learning objectives :
Data is presented showing how body fat distribution is a major determinant of a number of features related to the metabolic syndrome. Focus on intra-abdominal fat and its role in determining insulin sensitivity.

Bibliographic references :
Insulin resistance and fat patterning with aging: relationship to metabolic risk factors for cardiovascular disease.

Cefalu WT, Werbel S, Bell-Farrow AD, Terry JG, Wang ZQ, Opara EC, Morgan T, Hinson WH, Crouse JR 3rd.

Department of Internal Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC 27157-1047, USA.

Both insulin resistance and abdominal fat patterning are related to aging, and have been related to cardiovascular disease (CVD) risk factors such as dyslipidemia and hypertension. However, previous studies have not used direct methods to quantify the independent strength of the association of each of these two putative primary factors with metabolic outcomes. We quantified overall obesity by the body mass index (BMI) and used a previously validated magnetic resonance imaging (MRI) method to quantify abdominal fat in 63 healthy nondiabetic individuals aged 22 to 83 years. We also measured the glucose and insulin response to an oral glucose tolerance test and the insulin sensitivity ([SI] by modified minimal model analysis). Body fat patterning was evaluated by the waist to hip ratio (WHR) and by MRI, which allowed direct measurement of subcutaneous (SCF) and intraabdominal (IAF) fat depots at the umbilicus in these subjects. These independent parameters were related to risk factors for CVD (blood pressure, lipids, and lipoproteins) and to plasma concentrations of free fatty acids (FFAs). Measures of overall obesity (BMI), total fat [TF], and/or SCF measured at the abdomen by MRI), glucose/insulin metabolism and SI, and central fat patterning (WHR or IAF measured by MRI) were correlated with mean arterial pressure (MAP), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C) levels in univariate analysis and after controlling for age and gender. An index of central fat patterning (WHR) added to the informativeness of the insulin area under the curve (IAUC) in explaining 24% of the variability in plasma TG concentration, but measures of overall obesity were not independently related. Both the BMI and TF contributed to the IAUC in explaining 32% to 34% of the variability in MAP, but central fat patterning was not independently related. No index of overall obesity, fat patterning, glucose/insulin metabolism, and/or SI, was independently related to the plasma concentration of HDL-C after controlling for any one of the other two. Direct measurement of glucose/insulin metabolism and SI, as well as fat patterning, provides information on their relative associations with CVD risk factors. The measures of glucose/insulin metabolism and SI were more consistently related to dyslipidemia and hypertension than were the overall obesity and fat patterning in this healthy population.

Metabolism 1998 Apr;47(4):401-8

   


 Presentation 

"The Epidemic of Insulin Resistance and its Metabolic Consequences"

Prof. Bernard Zinman (biography)
English - 2002-04-27 - 27 minutes
(29 slides)

Summary :
Insulin resistance is a risk a factor for diabetes, and is changing all the time on a population level. We need to examine insulin resistance in context to obesity, the metabolic syndrome, type 2 diabetes, and IGT. The therapeutic challenge in treating type 2 diabetes now involves long-term glycemic control, increased insulin sensitivity, improved beta cell function, and medications which also...

Learning objectives :
The participant will learn how obesity has reached epidemic proportions and how it is contributing to insulin resistance and the metabolic syndrome.New guidelines for the treatment of type 2 diabetes are presented.

Bibliographic references :
Analysis of obesity and hyperinsulinemia in the development of metabolic syndrome: san antonio heart study.

Han TS, Williams K, Sattar N, Hunt KJ, Lean ME, Haffner SM.

Cambridge Clinical School, Cambridge, United Kingdom. Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas. University Department of Human Nutrition, Glasgow Royal Infirmary, Glasgow, United Kingdom.

OBJECTIVE: To use standardized cut-offs of body mass index (BMI), waist circumference, waist-to-hip ratio, and fasting insulin levels to predict the development of metabolic disorders and metabolic syndrome. RESEARCH
METHODS AND PROCEDURES: We performed an 8-year follow-up study of 628 non-Hispanic whites and 1340 Mexican Americans, ages 25 to 64 years, from the second cohort of the San Antonio Heart Study. We defined metabolic disorders as dyslipidemia (triglycerides >/=2.26 mM or high-density lipoprotein <0.91 mM in men and <1.17 mM in women), hypertension (blood pressure >/=140/>/=90 mm Hg, or receiving antihypertensive medications), and type 2 diabetes (fasting glucose >/=7.0 mM, 2-hour test glucose >/=11.1 mM, or receiving anti-diabetic medications). People with at least two metabolic disorders were defined as having metabolic syndrome.
RESULTS: High waist-to-hip ratio and fasting insulin levels were significant predictors of developing metabolic syndrome. High anthropometric indices remained significant predictors of metabolic syndrome after adjusting for fasting insulin. Waist circumference, BMI, and insulin had similar areas under the receiver operating characteristic curves (0.74 to 0.76). Further multivariate analyses combining these indices showed minimal increase in prediction. Of subjects who had a combination of high BMI (>/=30 kg/m(2)) and high waist circumference (above "Action Level 2"), 32% developed metabolic syndrome, compared with 10% of subjects with both low BMI and low waist circumference.
DISCUSSION: These findings support the National Institutes of Health recommendations for reducing the risk of metabolic syndrome. Adjustment for baseline fasting insulin levels had only a small effect on the ability of anthropometric indices to predict the metabolic syndrome.

Obes Res 2002 Sep;10(9):923-31

   


 Presentation 

"Panel Discussion: Insulin Resistance Versus Insulin Secretion: The Pathophysiology"

Dr. Stuart A Ross (biography)
English - 2002-04-27 - 27 minutes
(30 slides)

Summary :
Panel Discussion: Insulin Resistance Versus Insulin Secretion: The Pathophysiology
Moderator: Stuart Ross, MB
Participants:
Steve Kahn (MD), Daniel Porte Jr (MD) This Panel discussion was held at Lake Louise (Alberta) on April 27th, 2002, Chateau Lake Louise

Learning objectives :
Discussion on the pathophysiology and genetics of the metabolic syndrome, insulin resistance, insulin sensitivity, the "pre-diabetic" state, fat distribution; and the roles of molecules such as resistin and adiponectin.


Bibliographic references :
Adiponectin is not altered with exercise training despite enhanced insulin action.

Hulver MW, Zheng D, Tanner CJ, Houmard JA, Kraus WE, Slentz CA, Sinha MK, Pories WJ, MacDonald KG, Dohm GL.

Department of Physiology, East Carolina University, Greenville North Carolina 27858, USA. hulverm@mail.ecu.edu

Adiponectin is an adipocytokine that is hypothesized to be involved in the regulation of insulin action. The purpose of the present investigation was to determine whether plasma adiponectin is altered in conjunction with enhanced insulin action with exercise training. An insulin sensitivity index (S(I)) and fasting levels of glucose, insulin, and adiponectin were assessed before and after 6 mo of exercise training (4 days/wk for approximately 45 min at 65-80% peak O(2) consumption) with no loss of body mass (PRE, 91.9 +/- 3.8 kg vs. POST, 91.6 +/- 3.9 kg) or fat mass (PRE, 26.5 +/- 1.8 kg vs. POST, 26.7 +/- 2.2 kg). Insulin action significantly (P < 0.05) improved with exercise training (S(I) +98%); however, plasma adiponectin concentration did not change (PRE, 6.3 +/- 1.5 microg/ml vs. POST, 6.6 +/- 1.8 microg/ml). In contrast, in a separate group of subjects examined before and after weight loss, there was a substantial increase in adiponectin (+281%), which was accompanied by enhanced insulin action (S(I), +432%). These data suggest that adiponectin is not a contributory factor to the exercise-related improvements in insulin sensitivity.

Am J Physiol Endocrinol Metab 2002 Oct;283(4):E861-5

   


 Presentation 

"Panel Discussion: Is Insulin Resistance a Risk for Cardiovascular Disease? Two Perspectives"

Prof. Bernard Zinman (biography)
English - 2002-04-27 - 13 minutes
(12 slides)

Summary :
Moderator: Bernard Zinman, MD
Participants: Ehud Ur (MB), Amanda Adler (MB) This Panel discussion was held at Lake Louise (Alberta) on April 27th, 2002, Chateau Lake Louise

Learning objectives :
Discussion on how the nature of epidemiological studies and actual data gleaned helps or hinders the understanding of insulin resistance as a risk factor for CVD.


Bibliographic references :
Insulin resistance and atherosclerosis in diabetes mellitus.

Wollesen F, Berglund L, Berne C.

Department of Internal Medicine, Uppsala University Hospital, Uppsala, Sweden.

The aim of this study was to test our hypothesis that insulin resistance determines systemic atherosclerosis in type 2 diabetic patients. The design of the study was cross-sectional and included 28 type 2 patients with 48 type 1 patients as controls. The total daily insulin dose required to maintain glycosylated hemoglobin, HbA(1c), at 6.0% for 1 year was used as a measure of long-term insulin resistance. Systemic atherosclerosis was estimated by the toe systolic blood pressure index (TSPI). The results showed that total daily insulin dose was closely and independently associated with TSPI (r =.4652, partial P =.0064) in type 2 diabetic patients with secondary failure, even when adjusted for serum C-peptide (r =.4443, partial P =.00123). The association was absent in type 1 patients. Established risk factors were not associated with TSPI, but the products between individual risk factors and insulin dose were closely associated with TSPI. In conclusion, the daily insulin dose is associated with peripheral atherosclerosis in type 2 diabetic patients with high insulin resistance, but not in type 1 diabetes. The effect is additive to a lesser, underlying effect of established risk factors on atherosclerosis. Longstanding insulin resistance, as estimated by the daily insulin dose, is a determinant of atherogenesis. Copyright 2002, Elsevier Science (USA). All rights reserved.

Metabolism 2002 Aug;51(8):941-8


   


 Presentation 

"Insulin Resistance Is A Risk Factor For Cardiovascular Disease: YES"

Dr. Ehud Ur (biography)
English - 2002-04-27 - 43 minutes
(27 slides)
(30 slides)

Summary :
It is estimated that by year 2020 there will be approximately 250 million people affected by type 2 diabetes (DM2) worldwide. In Canada, the current prevalence is expected to double by that date. Although the underlying cause of diabetes is unknown, it is clear that insulin resistance (IR) plays a major role in the development and progression of the disease. Whilst IR can be seen as a molecular...

Learning objectives :
The participant will learn why insulin resistance is a risk factor for CVD, based on pathophysiology and epidemiological findings.


Bibliographic references :
Relationship between obesity, insulin resistance, and coronary heart disease risk.

Abbasi F, Brown BW Jr, Lamendola C, McLaughlin T, Reaven GM.

Department of Medicine, Stanford, California, USA

OBJECTIVES: The study goals were to: 1) define the relationship between body mass index (BMI) and insulin resistance in 314 nondiabetic, normotensive, healthy volunteers; and 2) determine the relationship between each of these two variables and coronary heart disease (CHD) risk factors. BACKGROUND: The importance of obesity as a risk factor for type 2 diabetes and hypertension is well-recognized, but its role as a CHD risk factor in nondiabetic, normotensive individuals is less well established.
METHODS: Insulin resistance was quantified by determining the steady-state plasma glucose (SSPG) concentration during the last 30 min of a 180-min infusion of octreotide, glucose, and insulin. In addition, nine CHD risk factors: age, systolic blood pressure, diastolic blood pressure (DBP), total cholesterol, triglycerides (TG), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein cholesterol concentrations, and glucose and insulin responses to a 75-g oral glucose load were measured in the volunteers. RESULTS: The BMI and the SSPG concentration were significantly related (r = 0.465, p < 0.001). The BMI and SSPG were both independently associated with each of the nine risk factors. In multiple regression analysis, SSPG concentration added modest to substantial power to BMI with regard to the prediction of DBP, HDL cholesterol and TG concentrations, and the glucose and insulin responses.
CONCLUSIONS: Obesity and insulin resistance are both powerful predictors of CHD risk, and insulin resistance at any given degree of obesity accentuates the risk of CHD and type 2 diabetes.

J Am Coll Cardiol 2002 Sep 4;40(5):937-43


   


 Presentation 

"Insulin action: The key roles of insulin receptor kinase (IRK) activation and internalization in effecting signaling"

Dr. Barry Posner (biography)
English - 2002-04-26 - 39 minutes
(28 slides)

Summary :
The insulin receptor (IR) is a heterotetrameric molecule consisting of two extracelleular alpha chains and two transmembrane beta chains linked by disulfide bonds. Each beta chain contains a tyrosine kinase activity in its cytosolic extension. The binding of a single insulin molecule into a pocket created by the two alpha chains effects a conformational change in the IR so that the beta chains...

Learning objectives :
The participant will gain insight into how the insulin signaling pathway itself might be involved in insulin resistance. Specifically, the internalization of the ligand-bound insulin receptor kinase (IRK) and its processing in the endosome sheds light on where the pathway might be flawed, thus leading to insulin resistance.


Bibliographic references :
Specific inhibition by hGRB10zeta of insulin-induced glycogen synthase activation: evidence for a novel signaling pathway.

Mounier C, Lavoie L, Dumas V, Mohammad-Ali K, Wu J, Nantel A, Bergeron JJ, Thomas DY, Posner BI.

The Polypeptide Hormone Laboratory, McGill University, Strathcona Building, 3640 University Street, Quebec, H3A 2B2, Montreal, Canada.

Grb10 is a member of a family of adapter proteins that binds to tyrosine-phosphorylated receptors including the insulin receptor kinase(IRK). In this study recombinant adenovirus was used to over-express hGrb10zeta, a new Grb10 isoform, in primary rat hepatocytes and the consequences for insulin signaling were evaluated. Over-expression of hGrb10zeta resulted in 50% inhibition of insulin-stimulated IRK autophosphorylation and activation. Analysis of downstream events showed that hGrb10zeta over-expression specifically inhibits insulin-stimulated glycogen synthase (GS) activity and glycogen synthesis without affecting insulin-induced IRS1/2 phosphorylation, PI3-kinase activation, insulin like growth factor binding protein-1 (IGFBP-1) mRNA expression, and ERK1/2 MAP kinase activity. The classical pathway from PI3-kinase through Akt-PKB/GSK-3 leading to GS activation by insulin was also not affected by hGrb10zeta over-expression. These results indicate that hGrb10zeta inhibits a novel and presently unidentified insulin signaling pathway leading to GS activation in liver.

Mol Cell Endocrinol 2001 Feb 28;173(1-2):15-27



   


 Presentation 

"Insulin Resistance and Islet Apoptosis"

Prof. Daniel J. Drucker (biography)
English - 2002-04-26 - 29 minutes
(2 slides)

Summary :
Type 2 diabetes is characterized by a combination of insufficient insulin
secretion and/or defective insulin action culminating in the development of
hyperglycemia and the metabolic syndrome associated with suboptimal control
of nutrient assimilation and disposal. Although hyperinsulinemia and
beta-cell hyperplasia are frequently seen early in the course of ...

Learning objectives :
- To understand the experimental models for studying beta cell death.
- To review the data contrasting apoptosis in rodent vs human beta cells/ animalmodels vs in vitro studies.
- To discuss the evidence supporting therapeutic intervention for restoration of beta cell mass and prevention of apoptosis.


Bibliographic references :
Biological actions and therapeutic potential of the glucagon-like peptides.

Drucker DJ.

The Banting and Best Diabetes Centre, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. d.drucker@utoronto.ca

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet beta cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of beta-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate-induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.

Gastroenterology 2002 Feb;122(2):531-44




   


 Presentation 

"Metabolic Complications of Insulin Resistance: Focus on lipid abnormalities"

Dr. Gary F. Lewis (biography)
English - 2002-04-26 - 43 minutes
(39 slides)

Summary :
Hyperlipidemia is a common consequence of the insulin-resistant state, and is felt to contribute significantly to the increased propensity to develop premature and aggressive atherosclerosis. The most common lipid abnormalities of diabetes and other insulin-resistant states are hypertriglyceridemia and reduction in the cholesterol content, and numbers of high density lipoprotein (HDL) particles....

Learning objectives :
Drawing largely on the research carried out in his own lab, Dr Lewis discusses the following:
1.Some mechanisms of HDL lowering in insulin resistant and type 2 diabetic conditions.
2.Mechanisms of overproduction of very low density lipoproteins (VLDLs) leading to hypertriglyceridemia.
3.Recent and unpublished work looking at intestinal lipoprotein overproduction in insulin resistant states.



Bibliographic references :
Fasting and Postprandial Overproduction of Intestinally Derived Lipoproteins in an Animal Model of Insulin Resistance. EVIDENCE THAT CHRONIC FRUCTOSE FEEDING IN THE HAMSTER IS ACCOMPANIED BY ENHANCED INTESTINAL DE NOVO LIPOGENESIS AND ApoB48-CONTAINING LIPOPROTEIN OVERPRODUCTION.

Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF, Adeli K.

Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children and the Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario M5G 1X8, Canada.

Insulin-resistant states are characterized by hypertriglyceridemia, predominantly because of overproduction of hepatic very low density lipoprotein particles. The additional contribution of intestinal lipoprotein overproduction to the dyslipidemia of insulin-resistant states has not been previously appreciated. Here, we have investigated intestinal lipoprotein production in a fructose-fed hamster model of insulin resistance previously documented to have whole body and hepatic insulin resistance, and hepatic very low density lipoprotein overproduction. Chronic fructose feeding for 3 weeks induced significant oversecretion of apolipoprotein B48 (apoB48)-containing lipoproteins in the fasting state and during steady state fat feeding, based on (a) in vivo Triton WR1339 studies of apoB48 production as well as (b) ex vivo pulse-chase labeling of intestinal enterocytes from fasted and fed hamsters. ApoB48 particle overproduction was accompanied by increased intracellular apoB48 stability, enhanced lipid synthesis, higher abundance of microsomal triglyceride transfer protein mass, and a significant shift toward the secretion of larger chylomicron-like particles. ApoB48 particle overproduction was not observed with short-term fructose feeding or in vitro incubation of enterocytes with fructose. Secretion of intestinal apoB48 and triglyceride was closely linked to intestinal enterocyte de novo lipogenesis, which was up-regulated in fructose-fed hamsters. Inhibition of fatty acid synthesis by cerulenin, a fatty acid synthase inhibitor, resulted in a dose-dependent decrease in intestinal apoB48 secretion. Overall, these findings further suggest that intestinal overproduction of apoB48 lipoproteins should also be considered as a major contributor to the fasting and postprandial dyslipidemia observed in response to chronic fructose feeding and development of an insulin-resistant state.

J Biol Chem 2002 Aug 30;277(35):31646-55

   


 Presentation 

"Cellular mechanisms of insulin resistance: Implications for type 2 diabetes and obesity"

Dr. Gerald Shulman (biography)
English - 2002-04-26 - 55 minutes
(53 slides)

Summary :
Insulin resistance is a major factor in the pathogenesis of type 2 diabetes ,and recent studies have demonstrated a strong relationship between increased plasma fatty acid concentrations and many insulin-resistant states, including obesity and type 2 diabetes mellitus. In a cross-sectional study of young normal-weight offspring of type 2 diabetic patients, we found an inverse relationship between...

Learning objectives :
This presentation focuses on recent studies using both 13C and 31P NMR techniques to examine the pathogenesis of insulin resistance in patients with type 2 diabetes mellitus. The specific biochemical questions addressed are:
1) Is the defect in muscle glycogen synthesis observed in patients with type 2 diabetes due to a block in glucose transport, hexokinase or glycogen synthase activity?
2) Is this defect primary or secondary in nature?
3) What is the mechanism of free fatty acid-induced insulin resistance?
These questions are explored in both human and novel transgenic mouse models.


Bibliographic references :
Effect of Weight Loss on Insulin Sensitivity and Intramuscular Long-Chain Fatty Acyl-CoAs in Morbidly Obese Subjects.

Houmard JA, Tanner CJ, Yu C, Cunningham PG, Pories WJ, MacDonald KG, Shulman GI.

Departments of Exercise and Sport Science, Surgery, and the Human Performance Laboratory and Diabetes/Obesity Center, East Carolina University, Greenville, North Carolina. Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut.

Increases in intramyocellular long-chain fatty acyl-CoAs (LCACoA) have been implicated in the pathogenesis of insulin resistance in skeletal muscle. To test this hypothesis, we measured muscle (vastus lateralis) LCACoA content and insulin action in morbidly obese patients (n = 11) before and after weight loss (gastric bypass surgery). The intervention produced significant weight loss (142.3 +/- 6.8 vs. 79.6 +/- 4.1 kg for before versus after surgery, respectively). Fasting insulin decreased by approximately 84% (23.3 +/- 3.8 vs. 3.8 +/- 0.5 mU/ml), and insulin sensitivity, as determined by minimal model, increased by approximately 360% (1.2 +/- 0.3 vs. 4.1 +/- 0.5 min(-1). [ micro U/kg(-1)]) indicating enhanced insulin action. Muscle palmityl CoA (16:0; 0.54 +/- 0.08 vs. 0.35 +/- 0.04 nmol/g wet wt) concentration decreased by approximately 35% (P < 0.05) with weight loss, whereas stearate CoA (18:0; -17%; 0.65 +/- 0.05 vs. 0.54 +/- 0.03 nmol/g wet wt) and linoleate CoA (18:2; -30%; 2.47 +/- 0.27 vs. 1.66 +/- 0.19 nmol/g wet wt) were also reduced (P < 0.05). There were no statistically significant declines in muscle palmitoleate CoA (16:1), oleate CoA (18:1), or total LCACoA content. These data suggest that a reduction in intramuscular LCACoA content may be responsible, at least in part, for the enhanced insulin action observed with weight loss in obese individuals.

Diabetes 2002 Oct;51(10):2959-2963


   


 Presentation 

"Vascular Insulin Resistance: The Syndrome X Files"

Dr. Ross Feldman (biography)
English - 2002-04-26 - 29 minutes
(25 slides)

Summary :
The relationship between insulin resistance and disordered vascular regulation predisposing to hypertension has been appreciated for more than a decade. The causal relationship linking these phenomenons remains unclear.

Initially, investigators in the field focused on the potential impact of hyperinsulinemia on vascular regulation. However, at least in regards to acute vascular...

Learning objectives :
The participant will learn how:
1. insulin mediates vasodilation
2. this vasodilation is disrupted by insulin resistance
3. vascular insulin resistance parallels both systemic insulin resistance and global indices of endothelial dysfunction
4. vascular insulin resistance is reversible


Bibliographic references :
The 2001 Canadian recommendations for the management of hypertension: Part one--Assessment for diagnosis, cardiovascular risk, causes and lifestyle modification.

Zarnke KB, McAlister FA, Campbell NR, Levine M, Schiffrin EL, Grover S, McKay DW, Myers MG, Wilson TW, Rabkin SW, Feldman RD, Burgess E, Bolli P, Honos G, Lebel M, Mann K, Abbott C, Tobe S, Petrella R, Touyz RM; Canadian Hypertension Recommendations Working Group.

London Health Sciences Centre, University Hospital Campus, London, Canada.

OBJECTIVE: To provide updated, evidence-based recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. OPTIONS: For persons in whom a high blood pressure value is recorded, hypertension is diagnosed based on the appropriate measurement of blood pressure, the level of the blood pressure elevation and the duration of follow-up. In addition, the presence of concomitant vascular risk factors, target organ damage and established atherosclerotic diseases must be assessed to determine the urgency, intensity and type of treatment. For persons receiving a diagnosis of hypertension, defining the overall risk of adverse cardiovascular outcomes requires an assessment of concomitant vascular risk factors, including laboratory testing, a search for target organ damage and an assessment for modifiable causes of hypertension. Home and ambulatory blood pressure assessment and echocardiography are options for selected patients. OUTCOMES: The outcomes were: the identification of persons at increased risk of adverse cardiovascular outcomes; the quantification of overall cardiovascular risk; and the identification of persons with potentially modifiable causes of hypertension. Evidence: Medline searches were conducted from one year before the period of the last revision of the Canadian recommendations for the management of hypertension (May 1999 to May 2001). Reference lists were scanned, experts were polled, and the personal files of the subgroup members and authors were used to identify other studies. Identified articles were reviewed and appraised, using prespecified levels of evidence, by content experts and methodological experts. In addition to an update of the previous year's review, new sections on assessing overall cardiovascular risk and endocrine causes are provided. VALUES: A high value was placed on the identification of persons at increased risk of cardiovascular morbidity and mortality, and of persons with identifiable causes of hypertension. BENEFITS, HARMS AND COSTS: The identification of persons at higher risk of cardiovascular disease will permit counseling for lifestyle manoeuvres and introduction of antihypertensive drugs to reduce blood pressure for patients with sustained hypertension. The identification of specific causes of hypertension may permit the use of cause-specific interventions. In certain subgroups of patients, and for specific classes of drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity or mortality. RECOMMENDATIONS: The present document contains recommendations for the assessment of the diagnosis, cardiovascular risk, identifiable causes and lifestyle modifications for adults with high blood pressure. These include the accurate measurement of blood pressure, criteria for the diagnosis of hypertension and recommendations for follow-up, assessment of overall cardiovascular risk, routine and optional laboratory testing, assessment for renovascular and endocrine causes, home and ambulatory blood pressure monitoring, the role of echocardiography and lifestyle modifications. VALIDATION: All recommendations were graded according to the strength of the evidence and voted on by the Canadian Hypertension Recommendations Working Group. Only those recommendations achieving high levels of consensus are reported. These guidelines will be updated annually. ENDORSEMENT: These guidelines are endorsed by the Canadian Hypertension Society, The Canadian Coalition for High Blood Pressure Prevention and Control, The College of Family Physicians of Canada, The Heart and Stroke Foundation of Canada, The Adult Disease Division and Bureau of Cardio-Respiratory Diseases and Diabetes at the Centre for Chronic Disease Prevention and Control, Health Canada.

Can J Cardiol 2002 Jun;18(6):604-24


   


 Presentation 

"Beta Cell Apoptosis and Diabetes"

Dr. Minna Woo (biography)
English - 2002-04-26 - 30 minutes
(29 slides)

Summary :
Insulin resistance and beta cell failure are the major culprits that contribute to development of diabetes mellitus. Over the last decade, much focus has been on the insulin resistance in the diabetes research arena. However, recently, insulin-producing beta cells have received attention in diabetes mellitus. Both animal and human data support the evidence of beta cell failure as a contributing...

Learning objectives :
The participant will learn about beta cell apoptosis: it's genetic foundations, physiologic and pathologic characteristics; and how it may contribute to diabetes types 1 and 2.


Bibliographic references :
Executionary pathway for apoptosis: lessons from mutant mice.

Woo M, Hakem R, Mak TW.

Amgen Institute and Ontario Cancer Institute, Department of Immunology, University of Toronto, Canada. mwoo@oci.utoronto.ca

Apoptosis or programmed cell death (PCD) is an evolutionarily conserved cellular process that is essential for normal development and homeostasis of multicellular organisms. Defects in the apoptosis signaling result in many diseases including autoimmune diseases and cancer. The apoptosis signaling pathway was first described genetically in the nematode Caenorhabditis elegans which serves as a framework for the more complex apoptotic pathways that exist in mammals. In this review, we will discuss the apoptotic pathways that are emerging in mammals as elucidated by studies of gene-targeted mutant mice.

Cell Res 2000 Dec;10(4):267-78


   


 Presentation 

"Panel discussion: Mechanisms of Insulin Resistance, Consequences of Insulin Resistance, Effects of Beta Cell Function"

Dr. Lawrence A. Leiter (biography)
English - 2002-04-26 - 30 minutes
(20 slides)

Summary :
Moderator:
- Lawrence A Leiter, MD, FRCPC, FACP
Participants:
- Gerald Shulman (MD), Barry Posner (MD), Daniel Drucker (MD) Gary Lewis (MD), Ross Feldman(MD), Minna Woo (MD)
This Panel discussion was held at Lake Louise (Alberta) on April 26th, 2002, Chateau Lake Louise

Learning objectives :
Discussion of insulin resistance and beta cell function, also looking at beta cell apoptosis and the role of FFAs.


Bibliographic references :
Islet amyloid, metabolic syndrome, and the natural progressive history of type 2 diabetes mellitus.

Hayden MR.

Department of Family and Community Medicine, University of Missouri School of Medicine. Columbia, Missouri, USA. mrh29@usmo.com

The presence of amyloid within the islet of the pancreas may be one of the best kept secrets in clinical medicine and translation of this century old finding may help to better understand the progressive nature of type 2 diabetes mellitus. Insulin resistance, metabolic syndrome, and type 2 diabetes mellitus are associated with multiple metabolic toxicities which result in an elevated tension of redox stress within the islet. Redox stress is associated with damage to proteins, lipids, and nucleic acids which may have a profound affect upon the structure and function of the islet. Earlier diagnosis at the stage of impaired glucose tolerance (prediabetes) and intervention may have a positive outcome on stabilization of the vulnerable islet and beta cell as well as the multiple diabetic complications. The natural history and a shift in the treatment paradigm of type 2 diabetes mellitus is explored as a result of these century old findings.

JOP 2002 Sep;3(5):126-38



   


 Presentation 

"Diabetes and CHD : Inflammation in Insulin Resistance (Academic and community specialists)"

Prof. Steven M. Haffner (biography)
English - 2002-04-11 - 47 minutes
(40 slides)

Summary :
Studies have shown a positive relationship between HbA1c and CHD. The pre-diabetic state may hold some clues as to how this correlation manifests itself. Some population subsets have a higher predisposition to insulin resistance. These people have worse cardiovascular risk factors than people who become diabetic due to low insulin secretion. Different diabetic medications also have different...

Learning objectives :
Upon this presentation, the participant should:
- learn the magnitude of the relationship of diabetes to coronary heart disease
- review the relationship of glycemia and insulin resistance to coronary heart disease
- review blood pressure and lipid lowering in diabetes

Bibliographic references :
Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the san antonio heart study.

Hanley AJ, Williams K, Stern MP, Haffner SM.

Division of Clinical Epidemiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas. Division of Epidemiology and Biostatistics, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario.

OBJECTIVE-The prospective association between insulin levels and risk of cardiovascular disease (CVD) is controversial. The objective of the present study was to investigate the relationship of the homeostasis model assessment of insulin resistance (HOMA-IR), as well as insulin levels, with risk of nonfatal and fatal CVD over the 8-year follow-up of the San Antonio Heart Study. RESEARCH DESIGN AND METHODS-Between 1984 and 1988, randomly selected Mexican-American and non-Hispanic white residents of San Antonio participated in baseline examinations that included fasting blood samples for glucose, insulin, and lipids, a glucose tolerance test, anthropometric measurements, and a lifestyle questionnaire. Between 1991 and 1996, 2,569 subjects who were free of diabetes at baseline were reexamined using the same protocol.
RESULTS-Over the follow-up period, 187 subjects experienced an incident cardiovascular event (heart attack, stroke, heart surgery, angina, or CVD death). Logistic regression analysis indicated that risk of a CVD event increased across quintiles of HOMA-IR after adjustment for age, sex, and ethnicity (P for trend <0.0001; quintile 5 vs. quintile 1, odds ratio [OR] 2.52, 95% CI 1.46-4.36). Additional adjustment for LDL, triglyceride, HDL, systolic blood pressure, smoking, alcohol consumption, exercise, and waist circumference only modestly reduced the magnitude of these associations (P for trend 0.02; quintile 5 vs. quintile 1, OR 1.94, 95% CI 1.05-3.59). Furthermore, there were no significant interactions between HOMA-IR and ethnicity, sex, hypertension, dyslipidemia, glucose tolerance (impaired glucose tolerance versus normal glucose tolerance), or obesity. The magnitude and direction of the relationship between insulin concentration and incident CVD were similar.
CONCLUSIONS-We found a significant association between HOMA-IR and risk of CVD after adjustment for multiple covariates. The topic remains controversial, however, and additional studies are required, particularly among women and minority populations.

Diabetes Care 2002 Jul;25(7):1177-84


   


 Presentation 

"Diabetes and CHD : Inflammation in Insulin Resistance (Community specialists and GPs)"

Prof. Steven M. Haffner (biography)
English - 2002-04-10 - 47 minutes
(40 slides)

Summary :
Studies have shown a positive relationship between HbA1c and CHD. The pre-diabetic state may hold some clues as to how this correlation manifests itself. Some population subsets have a higher predisposition to insulin resistance. These people have worse cardiovascular risk factors than people who become diabetic due to low insulin secretion. Different diabetic medications also have different...

Learning objectives :
Upon this presentation, the participant should:
- learn the magnitude of the relationship of diabetes to coronary heart disease
- review the relationship of glycemia and insulin resistance to coronary heart disease
- review blood pressure and lipid lowering in diabetes

Bibliographic references :
Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the san antonio heart study.

Hanley AJ, Williams K, Stern MP, Haffner SM.

Division of Clinical Epidemiology, University of Texas Health Sciences Center at San Antonio, San Antonio, Texas. Division of Epidemiology and Biostatistics, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario.

OBJECTIVE-The prospective association between insulin levels and risk of cardiovascular disease (CVD) is controversial. The objective of the present study was to investigate the relationship of the homeostasis model assessment of insulin resistance (HOMA-IR), as well as insulin levels, with risk of nonfatal and fatal CVD over the 8-year follow-up of the San Antonio Heart Study.
RESEARCH DESIGN AND METHODS-Between 1984 and 1988, randomly selected Mexican-American and non-Hispanic white residents of San Antonio participated in baseline examinations that included fasting blood samples for glucose, insulin, and lipids, a glucose tolerance test, anthropometric measurements, and a lifestyle questionnaire. Between 1991 and 1996, 2,569 subjects who were free of diabetes at baseline were reexamined using the same protocol. RESULTS-Over the follow-up period, 187 subjects experienced an incident cardiovascular event (heart attack, stroke, heart surgery, angina, or CVD death). Logistic regression analysis indicated that risk of a CVD event increased across quintiles of HOMA-IR after adjustment for age, sex, and ethnicity (P for trend <0.0001; quintile 5 vs. quintile 1, odds ratio [OR] 2.52, 95% CI 1.46-4.36). Additional adjustment for LDL, triglyceride, HDL, systolic blood pressure, smoking, alcohol consumption, exercise, and waist circumference only modestly reduced the magnitude of these associations (P for trend 0.02; quintile 5 vs. quintile 1, OR 1.94, 95% CI 1.05-3.59). Furthermore, there were no significant interactions between HOMA-IR and ethnicity, sex, hypertension, dyslipidemia, glucose tolerance (impaired glucose tolerance versus normal glucose tolerance), or obesity. The magnitude and direction of the relationship between insulin concentration and incident CVD were similar.
CONCLUSIONS-We found a significant association between HOMA-IR and risk of CVD after adjustment for multiple covariates. The topic remains controversial, however, and additional studies are required, particularly among women and minority populations.

Diabetes Care 2002 Jul;25(7):1177-84


   


 Presentation 

"Targeting Insulin Resistance in Type 2 Diabetes"

Prof. Harold Lebovitz (biography)
English - 2002-01-19 - 68 minutes
(33 slides)
(18 slides)
(2 questions)

Summary :
This presentation provides excellent training on insulin resistance. It is also about obesity issues, dealing with problems relating to free fatty acids, medication used under the circumstances and solutions to counter this dysfunction.

Learning objectives :
LEARNING OBJECTIVES:
After the presentation, the participants should:
1. Understand the role of insulin resistance in the pathogenesis of type 2 diabetes and as a risk factor for cardiovascular disease.
2. Know how to recognize the clinical feature.

Bibliographic references :
Treating hyperglycemia in type 2 diabetes: new goals and strategies.

Lebovitz HE.

Division of Endocrinology and Metabolism/Diabetes, State University of New York, SUNY Health Sciences Center, Brooklyn, USA.

To achieve glycemic goals in type 2 diabetes, one must usually use combinations of oral agents or oral agents plus insulin. This paper discusses the metabolic derangements of type 2 diabetes, the different classes of antihyperglycemic drugs, and strategies for using these drugs rationally.

Cleve Clin J Med 2002 Oct;69(10):809-20




   


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