Alterations in Immunoreactive Proinsulin and Insulin Clearance Induced by Weight Loss in NIDDM

Polonsky, Kenneth S.; Gumbiner, Barry M.; Ostrega, Diane; Griver, Kay; Tager, Howard S.; Henry, Robert R.

doi:10.2337/diab.43.7.871

Cited by 48 publications

(40 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…After secretion, insulin is removed from the plasma, mainly by the liver [28], in a process called insulin clearance, which is altered in obesity [29] and type 2 diabetes [2,30,31] animal models, and is also commonly associated with obesity [32,33] and type 2 diabetes in human patients [2,3,34]. It is well accepted that, in type 2 diabetes, insulin clearance is usually impaired and associated with insulin resistance and loss of beta cell mass.…”

Section: Discussionmentioning

confidence: 99%

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

et al. 2012

View full text Add to dashboard Cite

Aims/hypothesis Ciliary neurotrophic factor (CNTF) improves metabolic variables of obese animals with characteristics of type 2 diabetes, mainly by reducing insulin resistance. We evaluated whether CNTF was able to improve other metabolic variables in mouse models of type 2 diabetes, such as beta cell mass and insulin clearance, and whether CNTF has any effect on non-obese mice with characteristics of type 2 diabetes. Methods Neonatal mice were treated with 0.1 mg/kg CNTF or citrate buffer via intraperitoneal injections, before injection of 250 mg/kg alloxan. HEPG2 cells were cultured for 3 days in the presence of citrate buffer, 1 nmol/l CNTF or 50 mmol/l alloxan or a combination of CNTF and alloxan. Twenty-one days after treatment, we determined body weight, epididymal fat weight, blood glucose, plasma insulin, NEFA, glucose tolerance, insulin resistance, insulin clearance and beta cell mass. Finally, we assessed insulin receptor and protein kinase B phosphorylation in peripheral organs, as well as insulin-degrading enzyme (IDE) protein production and alternative splicing in the liver and HEPG2 cells. Results CNTF improved insulin sensitivity and beta cell mass, while reducing glucose-stimulated insulin secretion and insulin clearance in Swiss mice, improving glucose handling in a non-obese type 2 diabetes model. This effect was associated with lower IDE production and activity in liver cells. All these effects were observed even at 21 days after CNTF treatment. Conclusions/interpretation CNTF protection against type 2 diabetes is partially independent of the anti-obesity actions of CNTF, requiring a reduction in insulin clearance and increased beta cell mass, besides increased insulin sensitivity. Furthermore, knowledge of the long-term effects of CNTF expands its pharmacological relevance.

show abstract

Section: Discussionmentioning

confidence: 99%

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Increased insulin secretion has been observed in animal (26) and human (4,27) obesity. Insulin clearance was reduced in obesity (28)(29)(30)(31), insulin resistance without obesity (31), impaired glucose tolerance (IGT) (32), and diabetes (33). Decreased insulin clearance has also been observed with high-fat feeding in rats (34) and was suggested in a model of fat-fed dogs (19).…”

Section: Longitudinal Compensation For Fat Feedingmentioning

confidence: 99%

Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response.

et al. 2000

View full text Add to dashboard Cite

Central adiposity is highly correlated with insulin resistance, which is an important risk factor for type 2 diabetes and other chronic diseases. However, in normal individuals, central adiposity can be tolerated for many years without development of impaired glucose tolerance or diabetes. Here we examine longitudinally the mechanisms by which glucose tolerance can be maintained in the face of substantial insulin resistance. Normal dogs were fed a diet enriched with moderate amounts of fat (2 g · kg -1 · day -1 ), similar to that seen in modern "cafeteria" diets, and the time course of metabolic changes in these animals was examined over 12 weeks. Trunk adiposity as assessed by magnetic resonance imaging increased from 12 to 19%, but body weight remained unchanged. Insulin sensitivity (S I ) as determined by frequently sampled intravenous glucose tolerance tests was measured over a 12-week period. S I decreased 35% by week 1 and remained impaired for the entire 12 weeks. Intravenous glucose tolerance was reduced transiently for 1 week, recovered to baseline, and then again began to decline after 8 weeks. Firstphase insulin response began to increase after week 2, peaked by week 6 (190% of basal), and then declined. The increase in insulin response was due partially to enhanced ␤-cell function (22%) but due also to añ 50% reduction in insulin clearance. This compensation by insulin clearance was also confirmed with insulin clamps performed in fat-fed versus control dogs. The present study confirms the ability of the normal individual to compensate for fat-induced insulin resistance by enhanced insulin response, such that the product of insulin sensitivity ؋ secretion is little changed. However, the compensation is due as much to reduced insulin clearance as increased ␤-cell sensitivity to glucose. Reduced hepatic extraction of insulin may be the first line of defense providing a higher proportion of secreted insulin to the periphery and sparing the ␤-cells during compensation for the insulin-resistant state. Diabetes 49:2116-2125, 2000 T here is abundant evidence that diabetes and obesity are increasing in the U.S. population (1-3). Because adiposity is related to insulin resistance (4-6), and insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease, a consensus has emerged that increased adiposity is responsible for the increased incidence of type 2 diabetes and its associated morbidity (metabolic syndrome or syndrome X [7]). In addition, evidence has accumulated indicating that visceral adiposity in particular is associated with insulin resistance and the metabolic syndrome (8,9).Despite overwhelming evidence demonstrating association between insulin resistance, visceral adiposity, and metabolic risk, there is little evidence directly demonstrating that central adiposity in fact causes insulin resistance. In addition, there is little understanding of the mechanisms underlying the relationship among visceral adiposity, insulin resistance, and risk.To examine the acute effects of adiposi...

show abstract

“…Furthermore, as the loss of a first-phase insulin response is also found in patients with impaired glucose tolerance, this defect may be a pivotal early event in the natural history of Type 2 diabetes (8,19). Support for this hypothesis is also provided by the observation that the physiological prandial insulin response cannot be restored in patients with Type 2 diabetes even when insulin sensitivity is improved through weight loss (22).…”

Section: The Prandial Glucose Response In Type 2 Diabetesmentioning

confidence: 98%

[No Title Available]

Frandsen

Tambascia

1999

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

This article reviews the clinical evidence and pharmacological rationale for repaglinide, a prandial glucose regulator. Repaglinide has a rapid onset and short duration of action -a pharmacokinetic profile that allows administration in a flexible schedule at mealtimes to limit the postprandial blood glucose excursions typical of type 2 diabetes mellitus. Placebocontrolled and comparative studies of repaglinide have demonstrated that prandial repaglinide also achieves overall glycaemic control, indicated by essential blood glucose parameters such as fasting blood glucose and hemoglobin A1c (HbA1c) levels. Regulation of postprandial glucose is of clinical importance, as this is an important independent risk factor for diabetic complications. Glycaemic control has been further improved in patients with drug-resistant type 2 diabetes when repaglinide is incorporated into combination therapy regimens with insulin-sensitizing agents such as metformin or troglitazone. There are also data to suggest that a mealtime regimen of repaglinide can reduce the likelihood of hypoglycemia compared with traditional sulphonylurea-based regimens. This benefit may be particularly marked when the patient is free to adopt a varying meal pattern. While sulphonylureas can effectively improve overall glycaemic control, their prolonged action may result in inappropriate stimulation of beta-cells during periods of relatively low blood glucose, thereby incurring the risk of hypoglycemia. Although this risk can be reduced if meals are consumed at regular intervals, such an approach places restrictions on the patient's routine and freedom to implement lifestyle measures such as caloric restriction. Repaglinide is metabolized in the liver to inactive metabolites and excreted in bile, a potential advantage for patients with renal dysfunction. In conclusion, compelling reasons for considering a prandial approach to glycaemic management include risk reductions for diabetic complications and hypoglycemia, and greater flexibility for the patient. Available data concerning repaglinide suggest that many theoretical benefits of the prandial approach to glucose regulation may be achievable in clinical practice. RESUMOEste artigo revisa as evidências clínicas e farmacológicas para o uso da repaglinida, um regulador da glicose prandial. Repaglinida tem um iní-cio rápido de ação e curta duração -um perfil farmacocinético que permite sua administração em esquemas flexíveis no horário das alimentações limitando as flutuações pós-prandiais da glicemia, típicas do diabetes mellitus do tipo 2 (DM2). Estudos comparativos com repaglinida controlados por placebo demonstram que seu uso também controla os níveis médios da glicemia, conforme indicado por parâmetros essenciais de glicemia, como a glicemia de jejum e os níveis de hemoglobina A1c (HbA1c). O controle da glicemia pós-prandial é de grande importância clínica, uma vez que ela é um importante fator de risco

show abstract

Alterations in Immunoreactive Proinsulin and Insulin Clearance Induced by Weight Loss in NIDDM

Cited by 48 publications

References 17 publications

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

Ciliary neurotrophic factor (CNTF) protects non-obese Swiss mice against type 2 diabetes by increasing beta cell mass and reducing insulin clearance

Longitudinal compensation for fat-induced insulin resistance includes reduced insulin clearance and enhanced beta-cell response.

[No Title Available]

Contact Info

Product

Resources

About