Insulin resistance and obesity

It is well known that obesity, especially abdominal obesity, has a number of metabolic consequences, including insulin resistance (Frayn, 2005). Insulin resistance is a state that occurs when normal concentrations of insulin produce a subnormal biological response and the decay of glucose regulation, which eventually leads to type 2 diabetes (Krentz, 1996). Insulin sensitivity varies in healthy individuals, but obese individuals are very often insulin resistant (Frayn, 2005). 

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Mauriege P, Bouchard C. The Trp64Arg mutation in the / -adrenoreceptor gene of doubtful significance for obesity and insulin resistance. Lancet 1996 348 698-699. 

Kaaman M, Ryden M, Axelsson T, et al. (2006) ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance. Int J Obes (Land). 30, 447-452. 

Insulin resistance and obesity Obesity is the most common cause of insulin resistance. Most people with obesity and insulin resistance do not become diabetic. In the absence of a defect in p cell function, non-diabetic, obese individuals can compensate for insulin resistance with elevated levels of insulin. For example, Figure 25.7A shows that insulin secretion is two to three times higher in obese subjects than it is in lean individuals. This higher insulin concentration compensates for the diminished effect of the hormone (as a result of insulin resistance), and produces blood glucose levels similar to those observed in lean individuals (Figure 25.7B). 

Luef G, Abraham I, Haslinger M, Trinka E, Seppi K, Unterberger I, Alge A, Windisch J, Lechleitner M, Bauer G. Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A comparative study of carba-mazepine and valproic acid in 105 women. J Neurol 2002 249(7) 835-41. 

Huggins, K. W., Boileau, A. C., and Hui, D. Y. (2002) Protection against diet-induced obesity and insulin resistance in group IB PLA2 deficient mice. Am. J. Physiol. Endocrinol. Metab. 283, E994-E1001. 

Hotamisligil, G.S., Arner, P., Atkinson, R.L., and Spiegelman, B.M. 1997. Differential regulation of the p80 tumor necrosis factor receptor in human obesity and insulin resistance. Diabetes 46 451—455. 

Sartipy, R, and Loskutoff, D. J. 2003. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc. Natl. Acad. Sci., 100,7265-7270. 

Q4 In type 2 diabetes there is a reduction in the responsiveness of beta-cells (/1-cells) to plasma glucose levels (which might be due to a reduction in the number of (6-cells or their abnormal function) and an increase in the secretion of glucagon. Many patients with this condition show resistance insulin. Insulin resistance is defined as a suboptimal response to insulin in insulin-sensitive tissues (liver, muscle and adipose tissues). Insulin resistance is increased by obesity, inactivity and age. Obesity and insulin resistance coexist in approximately 60% to 80% of patients with type 2 diabetes in the West. In approximately 10% to 40% of patients with type 2 diabetes, amyloid deposits have been found in the islet tissues of the pancreas. Interestingly, the presence of amyloid correlates positively with the age of the patient and the duration and severity of the disease. 

Regulation of the body weight, is of great medical interest, because of the mutual interdependency of obesity and insulin resistance and its contribution to other systemic disease states, see ref. 49. Among the many factors that are involved in the complicated control of appetite and food consumption and the control of body weight, the leptins have received much attention. 

Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002 420 333-336. 

G.S. Hotamisligil, P. Arner, J.F. Caro, R.L. Atkinson, and B.M. Spiegelman, Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance, J. Clin. Invest., 1995, 95, 2409-2415. 

Insulin production by a normal, thin, healthy person is between 18 and 40 units/day ( 0.2-0.5 units/kg/day). About half this amount is secreted in the basal state and about half in response to meals. Thus, basal secretion is about 0.5—1 units/h after an oral glucose load, insulin secretion may increase to 6 units/h. In obese and insulin-resistant individuals, insulin secretion may be increased fourfold or more. 

McLaughlin T, Abbasi F, Lamendola C, et al. Differentiation between obesity and insulin resistance in the association with C-reactive protein. Circulation 2002 106 2908-2912. 

Polycystic ovary syndrome (PCOS) is characterized by menstrual irregularities, infertility, hyperandro-genism, obesity, and insulin resistance. In a study of rosiglitazone (4 mg twice daily for 2 months) with or without clomiphene in 25 women with PCOS who had not responded to clomiphene alone, ovulatory rates were higher in the combined versus monotherapy groups (77% and 33%, respectively) [53]. 

FIGURE 3.1 General features of MetS. Obesity and insulin resistance are causative factors in the development of the MetS. Insulin resistance and elevated blood pressure are related to cardiovascular diseases. 

Furthermore, adipose tissues were found to have some possible links between obesity and insulin resistance [89]. Obesity often causes insulin resistance, a decline in the ability of insulin to stimulate glucose uptake in the body leads to compensatory oversecretion of this hormone by the pancreatic cells and eventually, to cell exhaustion and development of type-2 diabetes mellitus [11,75]. Likewise in type-1 diabetes mellitus, the role of genetic factors has been studied to highlight the relation between inflammation, oxidant stress, and insulin insensitivity. Nuclear factor kappa B (NFkB) is a crucial transcription factor for response to oxidative stress and inflammation. Investigations about NFkB gene have shown its possible role in the susceptibility to type-1 diabetes by means of allelic differentiations, individuals with the AlO allele may be more likely to develop diabetes compared with those with the A14 allele [90]. 

Permana, P. A., DelParigi, A., and Tataranni, P. A., Microarray gene expression profiling in obesity and insulin resistance. Nutrition, 20,134-138, 2004. 

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