Defective insulin secretion in pancreatic β cells lacking type 1 IGF receptor

Xuan, Shouhong; Kitamura, Tadahiro; Nakae, Jun; Politi, Katerina; Kido, Yoshiaki; Fisher, Peter; Morroni, Manrico; Cinti, Saverio; White, Morris F.; Herrera, Pedro Luis; Accili, Domenico; Efstratiadis, Argiris

doi:10.1172/jci200215276

Cited by 43 publications

(19 citation statements)

References 66 publications

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“…Therefore, we stained adjacent sections with antiFoxo1 and anti-insulin, or anti-Pdx1 and anti-insulin antisera and carefully matched the position of β cells using insulin immunostaining to outline the nuclear margins (Figure 4b). On average, approximately 30% of cells showed matching nuclear "ghosts" in two adjacent 5-µm sections, consistent with the fact that the average β cell diameter is 10 µm and the nucleus occupies about 70% of the cell surface (6). In the vast majority of this subset of cells, Pdx1 and Foxo1 showed mutually exclusive nuclear localization.…”

supporting

confidence: 72%

“…However, the recent demonstration that insulin/IGF signaling plays a role in insulin secretion and β cell proliferation has led to a critical reassessment of this view (3). For example, inactivation of insulin receptor (Insr) (4) or IGF-1 receptor (Igf1r) (5,6) leads to impaired insulin secretion, while inactivation of insulin receptor substrate-2 (Irs2) impairs β cell proliferation (7,8). These observations indicate that peripheral insulin resistance and β cell failure may share a common pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

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The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth

Kitamura¹,

Nakae²,

Kitamura³

et al. 2002

J. Clin. Invest.

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422

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supporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth

Kitamura¹,

Nakae²,

Kitamura³

et al. 2002

J. Clin. Invest.

Self Cite

339

422

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“…The other was that conversely, insulin stimulated IGF-I synthesis or secretion as previously described [27, 28]. In fact, it has been shown that islet β-cell-specific inactivation of the IGF-IR gene caused an impairment in glucose-stimulated insulin release and glucose intolerance, despite no change in β-cell mass [35, 36], suggesting that circulating IGF-I has a positive effect on insulin secretion.…”

Section: Discussionmentioning

confidence: 68%

Low Serum IGF-I/GH Ratio Is Associated with Abnormal Glucose Tolerance in Acromegaly

Fukuoka

Takahashi²,

Iida³

et al. 2008

Horm Res Paediatr

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Background/Aims: Acromegaly is frequently accompanied with impaired glucose tolerance (IGT) and diabetes mellitus (DM). It remains unclear which factors determine the abnormal glucose tolerance status in acromegaly. In addition, diverse actions of GH and IGF-I in regulating glucose metabolism in acromegaly have not yet been well elucidated. The aim of this study was to investigate the factors associated with abnormal glucose tolerance in acromegaly. Subjects and Study Design: We conducted a retrospective cross-sectional study that included 48 patients with active acromegaly. The subjects were divided into two groups by the results of 75 g OGTT: normal glucose tolerance (NGT) group (n = 19) and IGT+DM group (n = 29). Results: Systolic blood pressure (SBP) was significantly higher in the IGT+DM than in the NGT group. Homeostasis model assessment of β-cell function (HOMA-β) was significantly decreased in the IGT+DM group compared with the NGT group. Although serum GH or IGF-I levels were not different between the two groups, the IGF-I/GH ratio in the IGT+DM group was significantly lower than that in the NGT group. Conclusions: We have shown that a low serum IGF-I/GH ratio was associated with abnormal glucose tolerance in acromegaly. We propose that the IGF-I/GH ratio is a useful marker to understand the metabolic status in acromegaly.

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“…The potential impact of plasma IGF1 levels on glucose homeostasis is complex. Targeted ablation of IGF1 receptors in pancreatic b cells in mice has been shown to impair glucose-induced insulin secretion (Xuan et al 2002), suggesting that IGF1 may have a role in the stimulation of insulin secretion, with lower IGF1 levels potentially Figure 10 Glucose, insulin, and glucagon levels (mean of levels from days 0 to 15 and from days 16 to 35) in male Lewis rats (nZ6 per group) after administration of pasireotide LAR 8 mg/kg on day 1 followed by octreotide LAR 8 mg/kg on day 16 or administration of octreotide LAR 8 mg/kg on day 1 followed by pasireotide LAR 8 mg/kg on day 16. A single injection of octreotide LAR or pasireotide LAR resulted in drug exposure for more than 35 days.…”

Section: Figurementioning

confidence: 99%

Effects of somatostatin analogs on glucose homeostasis in rats

Schmid

Brueggen²

2011

Journal of Endocrinology

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Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for sstr 1,2,3 and sstr 5 . The effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats were evaluated alone and in combination. Single-dose s.c. pasireotide acutely elevated plasma glucose, whereas single-dose s.c. octreotide had no or a small hypoglycemic effect. Glucose elevation with s.c. pasireotide was transient with tachyphylaxis after repeated or continuous administration. Pasireotide and octreotide caused similar inhibitory effects on insulin secretion, whereas pasireotide had a weaker inhibitory effect on glucagon secretion than octreotide. Continuous infusion of pasireotide or injection of pasireotide long-acting release (LAR) resulted in only small and transient elevations of plasma glucose. Based on these results, and differences in the sstr binding affinity of pasireotide vs octreotide, it was hypothesized that the sstr 5 vs sstr 2 receptor activation ratio is the main driver of hyperglycemia after pasireotide. The results also suggest that stronger activation of sstr 2 may counteract the hyperglycemic effect. Indeed, co-administration of octreotide, which has a high affinity for sstr 2 , with a hyperglycemic dose of pasireotide did not cause significant changes in plasma glucose levels. In conclusion, although pasireotide and octreotide inhibited insulin to a similar degree, only pasireotide administration was associated with hyperglycemia. The strong glucagon inhibitory effect exhibited by octreotide but not pasireotide may explain this observation. The lack of hyperglycemia during co-administration of pasireotide and octreotide may be explained by the greater activation of sstr 2 compared with pasireotide alone, causing the insulinglucagon balance to shift within the normoglycemic range. Extrapolation of these data to humans must account for species differences in islet cell sstr expression.

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Defective insulin secretion in pancreatic β cells lacking type 1 IGF receptor

Cited by 43 publications

References 66 publications

The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth

The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth

Low Serum IGF-I/GH Ratio Is Associated with Abnormal Glucose Tolerance in Acromegaly

Effects of somatostatin analogs on glucose homeostasis in rats

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