Interactions between insulin resistance and insulin secretion in the development of glucose intolerance

Cavaghan, Melissa K.; Ehrmann, David A.; Polonsky, Kenneth S.

doi:10.1172/jci10761

Cited by 325 publications

(230 citation statements)

References 39 publications

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“…Type 2 diabetes is characterized by both insulin resistance and b-cell dysfunction (Cavaghan et al 2000). It has been demonstrated that the b-cell dysfunction is related to chronic hyperglycemia and ER stress (Maedler et al 2003).…”

Section: Discussionmentioning

confidence: 99%

TRIB3 is implicated in glucotoxicity- and oestrogen receptor-stress-induced β-cell apoptosis

Qian¹,

Wang²,

Men³

et al. 2008

Journal of Endocrinology

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We found that TRIB3, an endogenous inhibitor of Akt (PKB), is expressed in pancreatic b-cells. The TRIB3 expression is significantly increased in islets isolated from hyperglycemic Goto-Kakizaki rats compared with normal glycemic controls. In vitro high glucose treatment also resulted in increased TRIB3 expression in rat INS1 cells. To investigate the role of TRIB3 in the regulation of b-cell function, we established an INS1 stable cell line allowing inducible expression of TRIB3. We demonstrated that overexpression of TRIB3 mimicked the glucotoxic effects on insulin secretion and cell growth in INS1 cells. Moreover, induction of TRIB3 also synergistically enhanced highglucose-elicited apoptosis in INS1 cells, whereas siRNA knock-down of TRIB3 showed the opposite effects. We also confirmed that the DJm of mitochondria was decreased, caspase-3 activity was up-regulated and reactive oxygen species content was increased in TRIB3 overexpressing b cells in high glucose condition. Most interestingly, the oestrogen receptor (ER) stress inducer, thapsigargin, mimicked the high glucose effects on up-regulation of TRIB3 and generation of apoptosis in cultured INS1 cells. These effects were specifically prevented by siRNA knock down of TRIB3. We therefore conclude that TRIB3 is implicated in glucotoxicity-and ER stress-induced b-cell failure. TRIB3 could be a potential pharmacological target for prevention and treatment of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

TRIB3 is implicated in glucotoxicity- and oestrogen receptor-stress-induced β-cell apoptosis

Qian¹,

Wang²,

Men³

et al. 2008

Journal of Endocrinology

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“…The 30-year controversy on whether type 2 diabetes is a disorder of reduced insulin action or diminished insulin secretion is abating, with most investigators accepting that diminished insulin secretion is a necessary condition for the development of impaired glucose homeostasis [3,[16][17][18]. The main reason for underestimating the deficit in insulin secretion is failure to recognise the modulating effect of insulin sensitivity on beta cell function [14].…”

Section: Discussionmentioning

confidence: 99%

K-value and low insulin secretion in a non-obese white population: predicted glucose tolerance after 25 years

et al. 2005

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Aims/hypothesis: Insulin resistance and insulin deficiency are proposed as risk factors for IGT and type 2 diabetes. We assessed the predictive value of initial parameters for the outcome of an OGTT performed 24.3±2.9 years later in an unselected healthy non-obese population. Methods: The K-value of an IVGTT was determined in 267 healthy subjects (mean±SD: age 31.0±12.0 years, BMI 21.8±2.8 kg/m 2 ). First-phase insulin response to a glucose infusion test was estimated as an incremental 5-or 10-min (ΔI5 or ΔI10) value, and as insulinogenic indices (ΔI5/ΔG5 or ΔI10/ΔG10) adjusted for insulin sensitivity determined by homeostasis model assessment for insulin resistance ([ΔI5/ΔG5]/HOMA-IR). Results: At followup, six subjects had type 2 diabetes and 47 had IGT; 214 retained normal glucose tolerance. Insulin sensitivity and early (30 min) insulin response decreased with decreasing outcome OGTT. Blood glucose (2 h) at OGTT correlated positively with initial age and BMI, and negatively with ΔI5/ΔG5, (ΔI5/ΔG5)/HOMA-IR and K-value. In multiple linear regression analysis, (ΔI5/ΔG5)/HOMA-IR, ΔI10, K-value, age, HOMA estimate of insulin secretion, and fasting plasma glucose were significantly associated with 2-h OGTT blood glucose. Similar results were obtained on comparing differences between subjects with normal and decreased (IGT+diabetes) glucose tolerance. Conclusions/interpretation: In 267 non-obese healthy subjects, initial K-value and first-phase insulin response to glucose adjusted for insulin sensitivity, but not insulin sensitivity itself, were strong predictors of the outcome of an OGTT performed 25 years later. Thus, in contrast to obese or other high-risk populations, in lean subjects, decreased beta cell function, but not insulin resistance itself, determines future glucose tolerance.

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“…Glucose-stimulated insulin secretion by perfused islets of 24-h fasted rats is reduced when compared with the response of islets from fed rats (Santos et al, 1989;Stein et al, 1996Stein et al, , 1997Koyama et al, 1997;Cavaghan et al, 2000). In rats deprived of food for 18-24 h, the ability of the b-cell to secrete insulin in response to a glucose load is fully dependent upon the elevated levels of circulating FFA characteristic of the fasted state (Stein et al, 1996).…”

Section: Plasma Fa and Insulin Secretionmentioning

confidence: 98%

Pleiotropic effects of fatty acids on pancreatic β‐cells

Haber

Ximenes

Procópio

et al. 2002

Journal Cellular Physiology

148

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Hyperlipidemia is frequently associated with insulin resistance states as found in type 2 diabetes and obesity. Effects of free fatty acids (FFA) on pancreatic b-cells have long been recognized. Acute exposure of the pancreatic b-cell to FFA results in an increase of insulin release, whereas a chronic exposure results in desensitization and suppression of secretion. We recently showed that palmitate augments insulin release in the presence of non-stimulatory concentrations of glucose. Reduction of plasma FFA levels in fasted rats or humans severely impairs glucose-induced insulin release. These results imply that physiological plasma levels of FFA are important for b-cell function. Although, it has been accepted that fatty acid oxidation is necessary for its stimulation of insulin secretion, the possible mechanisms by which fatty acids (FA) affect insulin secretion are discussed in this review. Long-chain acylCoA (LC-CoA) controls several aspects of the b-cell function including activation of certain types of protein kinase C (PKC), modulation of ion channels, protein acylation, ceramide-and/or nitric oxide (NO)-mediated apoptosis, and binding to nuclear transcriptional factors. The present review also describes the possible effects of FA on insulin signaling. We showed for the first time that acute exposure of islets to palmitate upregulates the intracellular insulin-signaling pathway in pancreatic islets. Another aspect considered in this review is the source of FA for pancreatic islets. In addition to be exported to the medium, lipids can be transferred from leukocytes (macrophages) to pancreatic islets in co-culture. This process consists an additional source of FA that may plays a significant role to regulate insulin secretion.

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Interactions between insulin resistance and insulin secretion in the development of glucose intolerance

Cited by 325 publications

References 39 publications

TRIB3 is implicated in glucotoxicity- and oestrogen receptor-stress-induced β-cell apoptosis

TRIB3 is implicated in glucotoxicity- and oestrogen receptor-stress-induced β-cell apoptosis

K-value and low insulin secretion in a non-obese white population: predicted glucose tolerance after 25 years

Pleiotropic effects of fatty acids on pancreatic β‐cells

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