In vivo insulin secretion and action in hyperglycemic rat

Laury, M C; Pénicaud, Luc; Ktorza, Alain; Benhaiem, H.; Picon, L

doi:10.1152/ajpendo.1989.257.2.e180

Cited by 16 publications

(13 citation statements)

References 15 publications

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“…Other laboratories have demonstrated similar adaptive physiology over the first 2-4 days of chronic glucose infusion in normal rats (20,40,41). Hager et al (15) showed diminished insulin sensitivity on day 3 relative to day 0, and although we could not directly compare insulin sensitivity during glucose infusion to day 0 before glucose infusion was begun, our data are consistent with these findings.…”

Section: Discussionsupporting

confidence: 87%

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Jamison¹,

Stark²,

Dong

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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GI, Kibbey RG. Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats. Am J Physiol Endocrinol Metab 301: E1174 -E1183, 2011. First published August 23, 2011; doi:10.1152/ajpendo.00175.2011.-Islet damage from glucose toxicity is implicated in the pathogenesis of type 2 diabetes, but the sequence of events leading to islet cell dysfunction and hyperglycemia remains unclear. To examine the early stages of islet pathology resulting from increased basal glucose loads, normal awake rats were infused with glucose continuously for 10 days. Plasma glucose and markers of islet and liver function were monitored throughout the infusion. After initial hyperglycemia, rats adapted to the infusion and maintained euglycemia for approximately 4 days. Continued infusion led to worsening hyperglycemia in just 5% of rats after 6 days, but 69% after 8 days and 89% after 10 days, despite unchanged basal and stimulated plasma insulin and C-peptide concentrations. In contrast, plasma glucagon concentrations increased fivefold. Endogenous glucose production (EGP) was appropriately suppressed after 4 days (2.8 Ϯ 0.7 vs. 6.1 Ϯ 0.4 mg·kg Ϫ1 ·min Ϫ1 on day 0, P Ͻ 0.001) but tripled between days 4 and 8 (9.9 Ϯ 1.7 mg·kg Ϫ1 ·min Ϫ1 , P Ͻ 0.01). Surprisingly, the increase in EGP was accompanied by increased mitochondrial phosphoenolpyruvate carboxykinase expression with appropriate suppression of the cytosolic isoform. Infusion of anti-glucagon antibodies normalized plasma glucose to levels identical to those on day 4 and ϳ300 mg/dl lower than controls. This improved glycemia was associated with a 60% reduction in EGP. These data support the novel concept that glucose toxicity may first manifest as ␣-cell dysfunction prior to any measurable deficit in insulin secretion. Such hyperglucagonemia could lead to excessive glucose production overwhelming the capacity of the ␤-cell to maintain glucose homeostasis. glucagon; hepatic glucose production; type 2 diabetes THE MECHANISMS THAT UNDERLIE THE EARLY STAGES of the progression to type 2 diabetes (T2D) are not fully understood. Inappropriately elevated endogenous glucose production (EGP) derived primarily from increased gluconeogenesis associated with hyperglucagonemia is an early feature in the progression to diabetes (16,27,28). Unlike the periodic and interrupted nature of prandial contributions to plasma glucose, EGP uniquely can contribute continuously to the glucose pool. Consequently, the sustained increase in insulin secretion throughout the day required to dispose of the increased EGP will increase the "basal workload" of islet cells. Although the mechanism is unclear, hyperglucagonemia has also been well documented in patients (2, 31, 33) and animal models (17,19,35,38) of diabetes with both hyper-and hypoinsulinemia, and it contributes to hyperglycemia by augmenting EGP. Because of the multiple physiological abnormalities in diabetic patients and most animal models, it is difficult to determine the relative contribution of h...

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Section: Discussionsupporting

confidence: 87%

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Jamison¹,

Stark²,

Dong

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Both mild and severe hyperglycemia in this spontaneously diabetic rat model appear to potentiate insulin secretion as reported previously in artificially hyperglycemic Wistar rats (28), rather than glucotoxicity and decreased p-cell function as reported by others (29,30). In the partial pancreatectomy dog model, glucose infusion caused impaired endogenous secretion after only 4 days, and islet loss also was shown (31).…”

Section: Discussionsupporting

confidence: 80%

Pancreatic Islet Function in Nondiabetic and Diabetic BB Rats

et al. 1993

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A decreased acute insulin response to glucose in islet cell antibody positive humans predicts diabetes. Because the dominant mechanism leading to decreased in vivo acute insulin response to glucose remains unclear, perifused islets were examined before and after diabetes onset in BB rats to assess the role of glucose sensitivity on insulin secretion in individual islets. Islets from normal WF rats, diabetes-prone rats without inflamed islets, diabetes-prone rats with inflamed islets, and diabetic rats were studied at 2.0, 8.3, and 16.7 mM glucose. Immunoreactive insulin from WF islets at 16.7 mM glucose was 0.15 +/- 0.02 ng.0-7 min-1 x islet-1 for the first phase and 1.00 +/- 0.05 ng.7-20 min-1 x islet-1 for the second phase of biphasic secretion, compared with basal secretion of 0.10 +/- 0.03 ng.20 min-1 x islet-1 at 2 mM glucose. Diabetes-prone noninflamed islets showed a 0.20 +/- 0.03 ng first-phase secretion, a 1.32 +/- 0.13 ng second-phase secretion after 16.7 mM glucose, and 0.093 +/- 0.02 ng.20 min-1 x islet-1 at 2 mM glucose, indicating no intrinsic BB rat strain secretion abnormality. Diabetes-prone inflamed islets had secretions of 0.35 +/- 0.02 ng during the first phase (P < 0.05 vs. WF) and 1.78 +/- 0.29 ng during the second phase (P < 0.05 vs. WF) after 16.7 mM glucose, with 0.24 +/- 0.08 ng.20 min-1 x islet-1 at 2 mM glucose.(ABSTRACT TRUNCATED AT 250 WORDS)

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“…Although insulin uptake is reportedly reduced during rat GI, yielding frank hyperglycemia (25), the rapid normalization of insulin levels in the present study could be the result of enhanced insulin clearance and/or increased insulin sensitivity under near-euglycemic conditions. The fact that another rat GI study clamping glucose levels at moderate hyperglycemia (170 mg/dl) observed increased tissue insulin sensitivity (24) suggests that this could be occurring in our model. We are currently addressing this possibility.…”

Section: Discussionmentioning

confidence: 84%

Enhanced β-cell mass without increased proliferation following chronic mild glucose infusion

Jetton

Everill²,

Lausier³

et al. 2008

American Journal of Physiology-Endocrinology and Metabolism

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The physiological mechanisms underlying pancreatic ␤-cell mass (BCM) homeostasis are complex and not fully resolved. Here we examined the factors contributing to the increased BCM following a mild glucose infusion (GI) whereby normoglycemia was maintained through 96 h. We used morphometric and immunochemical methods to investigate enhanced ␤-cell growth and survival in Sprague-Dawley rats. BCM was elevated Ͼ2.5-fold over saline-infused control rats by 48 h and increased modestly thereafter. Unexpectedly, increases in ␤-cell proliferation were not observed at any time point through 4 days. Instead, enhanced numbers of insulin ϩ cell clusters and small islets (400 -12,000 m 2 ; ϳ23-to 124-m diameter), mostly scattered among the acini, were observed in the GI rats by 48 h despite no difference in the numbers of medium to large islets. We previously showed that increased ␤-cell growth in rodent models of insulin resistance and pancreatic regeneration involves increased activated Akt/PKB, a key ␤-cell signaling intermediate, in both islets and endocrine cell clusters. GI in normal rats also leads to increased Akt activation in islet ␤-cells, as well as in insulin ϩ and insulin Ϫ cells in the common duct epithelium and endocrine clusters. This correlated with strong Pdx1 expression in these same cells. These results suggest that mechanisms other than proliferation underlie the rapid ␤-cell growth response following a mild GI in the normal rat and involve Akt-regulated enhanced ␤-cell survival potential and neogenesis from epithelial precursors.

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In vivo insulin secretion and action in hyperglycemic rat

Cited by 16 publications

References 15 publications

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Hyperglucagonemia precedes a decline in insulin secretion and causes hyperglycemia in chronically glucose-infused rats

Pancreatic Islet Function in Nondiabetic and Diabetic BB Rats

Enhanced β-cell mass without increased proliferation following chronic mild glucose infusion

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