PPARγ agonists in type 2 diabetes: how far have we come in ‘preventing the inevitable’? A review of the metabolic effects of rosiglitazone

Zinman, Bernard

doi:10.1046/j.1463-1326.2001.00033.x

Cited by 32 publications

(19 citation statements)

References 48 publications

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“…The beneficial metabolic effects of PPARg agonist treatment of human type II diabetics include 83 : (1) reduction in postprandial glucose, fasting plasma glucose and HbA1c, (2) increased insulin sensitivity and improved pancreatic island b-cell function; (3) increase in HDL levels and (variable) lowering of LDL levels; (4) lowering of diastolic blood pressure, decreased microalbuminuria, and increased levels of the fibrinolytic substances plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA).…”

mentioning

confidence: 99%

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

Larsen¹,

Toubro²,

Astrup³

2003

Int J Obes

258

170

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The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARg) is a member of the PPAR family. The endogenous activators of all members of the PPAR family are a variety of fatty acids, which suggests that the PPARs are highly involved in lipid metabolism. In the present paper, the current understanding of the involvement of PPARg in adipocyte proliferation and adipose tissue formation is extensively reviewed, and it is stressed that PPARg seems to be a major regulator in the differentiation of adipocytes. Thiazoledinediones (TZDs) are a group of PPARg-agonists used in the treatment of type 2 diabetes (T2D) since 1997. They are characterized by their ability to decrease insulin resistance, and have been suggested to slow down the progression of insulin resistance. Treatment with TZD requires several weeks of treatment to decrease plasma glucose levels, but in addition they markedly decrease plasma triglycerides and free fatty acids. A major drawback of treatment with TZD is body fat gain, but some evidence suggests that the fat is redistributed in a favourable direction, that is, from visceral to subcutaneous depots. However, the effect of long-term treatment on weight gain following TZD treatment is unknown, and it may be questioned whether the use of these 'adipogenic compounds' is appropriate, considering that excess body fat is almost a prerequisite for the development of type 2 diabetes.

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mentioning

confidence: 99%

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

Larsen¹,

Toubro²,

Astrup³

2003

Int J Obes

258

170

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“…61 This effect on ␤-cell function is supported by reductions in the PI:insulin ratio, suggesting that the ␤-cell is able to process insulin precursors more efficiently. 62 Preclinical studies indicate that rosiglitazone enhances the insulin secretory response by a mechanism involving PI 3-kinase activation. 63 It is possible that this effect on ␤-cell function is mediated through changes in FFA levels-sustained reductions of up to 34% have been observed in studies with rosiglitazone.…”

Section: Clinical Benefits Of Thiazolidinedionesmentioning

confidence: 99%

“…Importantly, studies with rosiglitazone have shown that glycemic control can be achieved with these agents in a wide range of patient groups and ethnic populations. 62,[72][73][74][75][76] …”

Section: Clinical Benefits Of Thiazolidinedionesmentioning

confidence: 99%

Targeting Insulin Resistance and β-Cell Dysfunction: The Role of Thiazolidinediones

Prato

Marchetti²

2004

Diabetes Technology & Therapeutics

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Insulin resistance and beta-cell dysfunction are fundamental defects that contribute to the development of type 2 diabetes, and as such are targets for primary prevention of disease progression. The two parameters are linked by several factors, including glucotoxicity and lipotoxicity, and recent research has enlightened understanding of the molecular mechanisms underlying the development and progression of the disease. Historically, type 2 diabetes has been managed by controlling hyperglycemia, using agents that increase insulin levels or reduce hepatic glucose production, as exemplified by the United Kingdom Prospective Diabetes Study. The thiazolidinediones control hyperglycemia by targeting the fundamental defects of the disease, and have shown well-documented improvements in insulin sensitivity and beta-cell function, both in monotherapy and in combination with other oral antidiabetic agents. TRoglitazone In the Prevention Of Diabetes (TRIPOD) has demonstrated the potential for thiazolidinediones to delay progression to type 2 diabetes. Prospective studies such as Diabetes REduction Approaches with ramipril and rosiglitazone Medications (DREAM) are currently evaluating the long-term effects of thiazolidinediones on metabolic status and disease progression.

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“…Importantly, open-label extensions of some of the controlled trials with rosiglitazone show that improved glycaemic control is maintained for at least 30 months when used in monotherapy and for upwards of 24 months, when used in combination with metformin [34]. Long-term, head-to-head, controlled studies, such as A Diabetes Outcome Progression Trial (ADOPT) [35], will establish whether agents like rosiglitazone are superior to metformin and sulfonylureas in providing sustained glycaemic control.…”

Section: Clinical Profile Of Thiazolidinedione Ppar-γ Agonistsmentioning

confidence: 99%

Insulin sensitisation in the treatment of Type 2 diabetes

Tadayyon

Smith

2003

Expert Opinion on Investigational Drugs

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Type 2 diabetes is reaching epidemic proportions worldwide, fueled by the increasing prevalence of obesity as many populations adopt a western lifestyle. Secondary complications affecting both the microvascular and macrovascular systems are responsible for premature mortality in Type 2 diabetes, with two thirds or more dying of cardiovascular disease. Two interacting metabolic defects, insulin resistance and beta-cell dysfunction are present in Type 2 diabetes. It is now recognised that insulin resistance is central to a cluster of metabolic abnormalities--called the insulin resistance syndrome--that are responsible for the excess of cardiovascular disease. Older antidiabetic agents such as the sulfonylureas, metformin and insulin are more effective than lifestyle modification in reducing microvascular complications of Type 2 diabetes, but overall do not reduce cardiovascular risk. Metformin, although no more effective as a glucose-lowering agent than sulfonylureas or insulin, does significantly reduce cardiovascular disease, probably as a result of its weak insulin-sensitising action. The newly-marketed thiazolidinedione insulin-sensitising antidiabetic agents also improve multiple biomarkers of cardiovascular risk, suggesting that novel approaches to insulin sensitisation will not only provide effective long-term glycaemic control but improve cardiovascular outcomes in Type 2 diabetes. Multiple therapeutic targets within the insulin signalling cascade are being explored, together with follow-up compounds to the first generation thiazolidinediones. These initiatives, together with developments in beta(3)-adrenoceptor agonists, 11 beta-hydroxysteroid dehydrogenase Type 1 inhibitors and modulators of the glucagon-like peptide 1 axis, all of which also potentially enhance insulin sensitivity, are critically evaluated.

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PPARγ agonists in type 2 diabetes: how far have we come in ‘preventing the inevitable’? A review of the metabolic effects of rosiglitazone

Cited by 32 publications

References 48 publications

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

Targeting Insulin Resistance and β-Cell Dysfunction: The Role of Thiazolidinediones

Insulin sensitisation in the treatment of Type 2 diabetes

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