Insuhn resistance

McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA. Altered glycan-dependent signaling induces insuhn resistance and hyperleptinemia. Proc. Natl. Acad. Sci. U.S.A. 2002 99 10695-10699. 

Das UN. Insuhn resistance and hyperinsulinemia Are they secondary to an alteration in the metabolism of essential fatty acids Med. Sci. Res. 1994 22 243-245. 

A few patients treated with insuhn aspart developed antibodies, which cross-reacted with antibodies against human insuhn and fell after 3 months (19). In lipodystrophy with lipoatrophic diabetes high insuhn resistance is often found, for which leptin deficiency is one contributory factor. 

Fronton S, Choi SB, Banduch D, Rossetti L, In vivo insuhn resistance induced by amylin primarily through inhibition of insulin-stimulated glycogen synthesis in skeletal muscle. Diabetes 1991 40 568-73. 

Ginsberg HN. Insuhn resistance and cardiovascular disease. J Clin Invest 2000 106 453-8. 

A beneficial response of glucose-intolerant patients to chromium supplementation is presently the only means of confirming chromium deficiency. No practicable method of assessing intracellular chromium depletion is yet available and there is no consistently reliable animal model for chromium deficiency. Furthermore, it has been known from early animal experiments that circulating chromium is not in equihbrium with physiologically important reserves. It has been shown in late pregnancy that serum chromium concentration does not correlate with glucose intolerance, insuhn resistance, or serum hpids. ... 

The design and use of insuUn-like molecules acting downstream insuhn receptor might be useful in treating insuhn-resistance states in this context, IPG is a good candidate molecule as an alternative to insuhn treatment The abihty of IPG to mimic insuhn actions is certainly striking. Tab. 6.2 summarises insuhn-hke effects of IPG on both intact ceUs and cellular extracts [2-5, 8, 10, 32, 34, 72-74]. 

Cardiomyocytes are known to express HSL [68, 78, 79 see below] and the hormone-responsiveness of myocardial lipolysis suggests that HSL is probably responsible. In addition, the heart can synthesize and secrete apoB-containing lipoproteins [3]. If, as apparently with the liver, endogenous TAG is mobilized for lipoprotein assembly via a lipolytic event the question arises can HSL fulfil this function in the heart or is another lipase involved in a mechanism identical to that in the liver It has been proposed that mobilization of endogenous cardiac TAG for lipoprotein secretion provides the heart with a safety valve to dispose of excess lipid [3] and thus protects against lipotoxicity [65]. Lipoapoptosis observed in the heart leads to the development of heart failure [80, 81]. If, as apparently with skeletal muscle [82], excess TAG accumulation plays a role in insuhn resistance, hpoprotein secretion may enable cardiac muscle insuhn sensitivity in the face of an excessive flux of FA. 

Of the various factors suggested to play a part in impaired adipocyte function in insuhn resistance and NIDDM, increased TNF-a expression and production have attracted interest. TNF-a is produced and secreted from adipose tissue in obesity and thus acts in an autocrine fashion to alter adipocyte function during obesity-hnked insuhn resistance [385-387]. Long-term exposure (>6h) to TNF-a has been shown to stimulate hpolysis in adipocytes [368, 388], despite inducing reduced HSL expression [389, 390]. An early study showed a down-regulation of HSL gene expression upon TNF-a treatment of 3T3-L1 cells, as measured by Northern blot analysis and enzyme activity measurements [391]. A similar effect, although much more moderate, was seen more recenfly at the protein level [264]. In a study wifh primary rat adipocytes, however, no alteration of the levels of HSL protein occurred upon treatment wifh TNF-a [392]. 

B.M. Spiegelman, Uncoupling of obesity from insuhn resistance through a targeted mutation in aP2, the adipocyte fatty acid binding protein. Science, 1996, 274, 1377-1379. 

Several genetic mutations have been described in the insuhn receptor and are associated with insulin resistance. Type A insuhn resistance refers to the clinical syndrome of acanthosis nigricans, virilization in women, polycystic ovaries, and hyperinsulinemia. Leprechaunism is a pediatric syndrome with specific facial features and severe insulin resistance due to a defect in the insuhn receptor gene. Lipoatrophic diabetes probably results from postreceptor defects in insulin signaling. 

Type 2 diabetic individuals are characterized by (1) defects in insulin secretion and (2) insulin resistance involving muscle, hver, and the adipocyte. Insuhn resistance is present even in lean type 2 diabetic individuals (Fig. 72-5). 

Insuhn resistance and the components of the insulin resistance syndrome are described below. 

The term visceral adipose tissue (VAT) refers to fat cells located within the abdominal cavity and includes omental, mesenteric, retroperitoneal, and perinephric adipose tissue. VAT has been shown to correlate with insuhn resistance and explain much of the variation in insuhn resistance seen in a population of African-Americans. Visceral adipose tissue represents 20% of fat in men and 6% of fat in women. This fat tissue has been shown to have a higher rate of lipolysis than subcutaneous fat, resulting in an increase in free fatty acid production. These fatty acids are released into the portal circulation and drain into the liver, where they stimulate the production of very-low-density lipoproteins and decrease insuhn sensitivity in peripheral tissues. VAT also produces a number of cytokines which cause insulin resistance. These factors drain into the portal circulation and reduce insulin sensitivity in peripheral tissues. ... 

The association of insulin resistance with a clustering of cardiovascular risk factors including hyperinsuhnemia, hypertension, abdominal obesity, dyslipidemia, and coagulation abnormahties has been referred to by a variety of names including the insuhn resistance syndrome, the metabolic syndrome, the dysmetabolic syndrome, and the deadly quartet, to name a few. Since the description of the insulin resistance syndrome by Reaven in 1988, the number of associated factors has continued to grow. 

As a rough estimate, patients may be begun on 0.6 units/kg per day with basal insuhn 50% of total dose and prandial insuhn 20% of total dose prebreakfast, 15% prelunch, and 15% presupper. Type 1 DM patients generally require between 0.5 and 1 unit/kg per day. The need for signiflcantly higher amounts of insuhn suggests the presence of insuhn antibodies or insuhn resistance (coexistent endocrinopathy or type 2 DM). 

Figure 22-3. Schematic diagram showing the effects of insuhn resistance leading to diabetes melhtus.

Kabayama, K., Sato, T., Saito, K., Loberto, N., Prinetti, A., Sonnino, S., Kinjo, M., Igarashi, Y. and Inokuchi, J., Dissociation of the insuUn receptor and caveolin-1 complex by ganglioside GM3 in the state of insuhn resistance, Proc Natl Acad Sci USA 104 (2007) 13678-13683. 

Type II diabetes is slow to develop (typically in older, obese individuals), and the symptoms are milder and often go unrecognized at first. This is really a group of diseases in which the regulatory activity of insulin is defective insulin is produced, but some feature of the insulin-response system is defective. These individuals are insuhn-resistant. The connection between type II diabetes and obesity (discussed below) is an active area of research. 

REGULATION OF GENE TRANSCRIPTION A major action of insulin is the regulation of transcription of more than 100 specific genes. InsuMn inhibits the transcription of phosphoenolpyruvate carboxykinase, contributing to insulin s inhibition of gluconeogenesis this effect of insulin may explain why the liver overproduces glucose in the insuhn-resistant state that is characteristic of type 2 DM. 

Yamauchi, T. et al. The mechanism by which both heterozygous peroxisome proliferator-activated receptor 7 (PPAR7) and PPAR7 agonist improve insuhn resistance. J. Biol. Chem. 2001, 276, 41245 1254. 

McLaughlin T, Abbasi F, Cheal K, et al. Use of meta-bohc markers to identify overweight individuals who are insuhn resistant. Ann Intern Med 2003 139 802-809. 

Abbasi F, Chang S-A, Chu JW, GM, Improvements in insuhn resistance with weight loss, in contrast to rosightazone, is not correlated with changes in plasma adiponectin or adiponectin multimeric complexes. Am J Physiol Integr Comp Physiol 2006 290 R 139-144, 47. 

Cataldo NA, Abbasi F, Mclaughlin TL, et al. Metabohe and ovarian effects of rosightazone treatment for 12 weeks in insuhn-resistant women with polycystic ovary syndrome. Hum Repro 2006 1 109-120. 

Reaven GM. Compensatory hyperinsulinemia and the development of an atherogenic lipoprotein profile the price paid to maintain glucose homeostasis in insuhn-resistant individuals. Endocrinol Metab Chn N Am. 2005 34 49-62. 

Robins SJ, Rubins HB, Pass PH, et al. Insuhn resistance and cardiovascular events with low HDD cholesterol the Veterans Affairs HDD Intervention Trial (VA-HIT). Diabetes Care 2003 26 1513-1517. 

Improvement in the insuhn resistance that under-hes the pathogenesis of type 2 diabetes and the metabolic syndrome leads to pleiotropic effects, including reduced glycemia, enhanced beta cell function, reduction in the inflammatory milieu, improvement in dyshpidemia and blood pressure vascular endothehal function, cardiovascular risk reduction, and in the prevention of diabetes. 

---