Regulation of α-Cell Function by the β-Cell During Hypoglycemia in Wistar Rats: the “Switch-off” Hypothesis

Zhou, Huarong; Tran, Phuong Oanh T.; Yang, Shilin; Zhang, Tao; Leroy, Éric; Oseid, Elizabeth; Robertson, R. P.

doi:10.2337/diabetes.53.6.1482

Cited by 97 publications

(107 citation statements)

References 44 publications

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“…This is consistent with previous studies in patients with type 1 diabetes showing a clear relationship between beta cell function and HbA 1c levels during glucose-lowering treatment [27,28]. The mechanisms underling this association have not been completely clarified yet, but may involve the effects of endogenous insulin on alpha cell function [29][30][31] as well as the direct intra-portal drainage of endogenous insulin vs systemic delivery of exogenously administered insulin [32]. Taken together, these studies emphasise the importance of endogenous insulin secretion for glucose control and support the concept of enhancing beta cell function in the treatment of patients with diabetes [33].…”

Section: Discussionsupporting

confidence: 92%

Determinants of glucose control in patients with chronic pancreatitis

et al. 2010

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Aims/hypothesis Diabetes frequently develops in patients with chronic pancreatitis (CP). Partial pancreatectomy has emerged as a treatment option for such patients. We addressed whether the development of diabetes in CP patients is related to pancreatic beta cell area or clinical variables, and which factors predict the diabetes risk after partial pancreatectomy. Methods Fractional beta cell area was determined in pancreatic tissue samples obtained from 114 CP patients undergoing pancreatic surgery and related to measures of glucose control, as well as clinical and anthropometric data. Seventy-four patients without diabetes at the time of surgery were contacted again 2.5±1.0 years after partial pancreatectomy in order to obtain information about the post-operative development of diabetes. Results In the surgical samples in the whole cohort, pancreatic beta cell area was 0.40±0.06% in patients with and 0.64±0.06% in those without previously known diabetes (p=0.039). There was an inverse non-linear relationship between pancreatic beta cell area and fasting glucose concentrations (r=0.29) as well as HbA 1c levels (r=0.36). Nineteen out of 74 previously normoglycaemic patients (26%) developed diabetes over an average period of 2.5 years of follow-up. Pre-operative fasting glucose levels, HbA 1c and BMI were identified as predictors of diabetes after partial pancreatectomy. However, pancreatic beta cell area did not differ in those who subsequently developed diabetes (0.66±0.15%) and those who did not (0.62± 0.08%, p=0.45). Conclusions/interpretation Hyperglycaemia in CP patients is associated with reduced beta cell area. However, reduced beta cell area does not predict the development of diabetes, suggesting that other factors are more important determinants of alterations in glucose metabolism in patients with CP.

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Section: Discussionsupporting

confidence: 92%

Determinants of glucose control in patients with chronic pancreatitis

et al. 2010

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“…Consequently, both low glucose concentrations and switching off ␣-cell exposure to insulin are required for the glucagon response. These conclusions are supported by the findings reported in the accompanying work by Zhou et al (16), which describes in vivo experiments using STZ-administered rats receiving regional insulin infusions via the pancreaticoduodenal artery.…”

Section: Discussionsupporting

confidence: 81%

“…Both normal male Wistar rats and rats made diabetic by injections of 80 mg/kg STZ were used (16). Two weeks were allowed to elapse after the STZ injection.…”

Section: Methodsmentioning

confidence: 99%

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

et al. 2004

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The "switch-off" hypothesis to explain ␤-cell regulation of ␣-cell function during hypoglycemia has not been assessed previously in isolated islets, largely because they characteristically do not respond to glucose deprivation by secreting glucagon. We examined this hypothesis using normal human and Wistar rat islets, as well as islets from streptozotocin (STZ)-administered ␤-celldeficient Wistar rats. As expected, islets perifused with glucose and 3-isobutryl-1-methylxanthine did not respond to glucose deprivation by increasing glucagon secretion. However, if normal rat islets were first perifused with 16.7 mmol/l glucose to increase endogenous insulin secretion, followed by discontinuation of the glucose perifusate, a glucagon response to glucose deprivation was observed (peak change within 10 min after switch off ‫؍‬ 61 ؎ 15 pg/ml [mean ؎ SE], n ‫؍‬ 6, P < 0.01). A glucagon response from normal human islets using the same experimental design was also observed. A glucagon response (peak change within 7 min after switch off ‫؍‬ 31 ؎ 1 pg/ml, n ‫؍‬ 3, P < 0.01) was observed from ␤-cell-depleted, STZ-induced diabetic rats whose islets still secreted small amounts of insulin. However, when these islets were first perifused with both exogenous insulin and 16.7 mmol/l glucose, followed by switching off both the insulin and glucose perifusate, a significantly larger (P < 0.05) glucagon response was observed (peak change within 7 min after switch off ‫؍‬ 71 ؎ 11 pg/ml, n ‫؍‬ 4, P < 0.01). This response was not observed if the insulin perifusion was not switched off when the islets were deprived of glucose or when insulin was switched off without glucose deprivation. These data uniquely demonstrate that both normal, isolated islets and islets from STZ-administered rats can respond to glucose deprivation by releasing glucagon if they are first provided with increased endogenous or exogenous insulin. These results fully support the ␤-cell switch-off hypothesis as a key mechanism for the ␣-cell response to hypoglycemia.

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“…Recently, we demonstrated this phenomenon directly in vivo in streptozotocin-induced diabetic rats and in vitro using isolated islets from these animals. In the in vivo studies, an insulin infusion into the pancreatic artery was switched off when the animals were made hypoglycemic by a jugular-vein infusion of insulin (4).…”

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confidence: 99%

Zinc, Not Insulin, Regulates the Rat α-Cell Response to Hypoglycemia In Vivo

et al. 2007

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The intraislet insulin hypothesis proposes that the decrement in ␤-cell insulin secretion during hypoglycemia provides an activation signal for ␣-cells to release glucagon. A more recent hypothesis proposes that zinc atoms suppress glucagon secretion via their ability to open ␣-cell ATPsensitive K ؉ channels. Since insulin binds zinc, and zinc is cosecreted with insulin, we tested whether decreased zinc delivery to the ␣-cell activates glucagon secretion. In streptozotocin-induced diabetic Wistar rats, we observed that switching off intrapancreatic artery insulin infusions in vivo during hypoglycemia greatly improved glucagon secretion (area under the curve [AUC]: control group 240 ؎ 261 and experimental group 4,346 ؎ 1,259 pg ⅐ ml ؊1 ⅐ 90 min ؊1 ; n ‫؍‬ 5, P < 0.02). Switching off pancreatic artery infusions of zinc chloride during hypoglycemia also improved the glucagon response (AUC: control group 817 ؎ 107 and experimental group 3,445 ؎ 573 pg ⅐ ml ؊1 ⅐ 90 min ؊1 ; n ‫؍‬ 6, P < 0.01). However, switching off zinc-free insulin infusions had no effect. Studies of glucose uptake in muscle and liver cell lines verified that the zinc-free insulin was biologically active. We conclude that zinc atoms, not the insulin molecule itself, provide the switch-off signal from the ␤-cell to the ␣-cell to initiate glucagon secretion during hypoglycemia. Diabetes 56:1107-1112, 2007 G lucagon secretion into the hepatic portal circulation is critical for counterregulation of hypoglycemia by virtue of its stimulatory effect on hepatic glycogenolysis, which releases glucose into the systemic circulation to return blood glucose to normal levels. The decrement in insulin release from ␤-cells has been proposed to signal the ␣-cell to release glucagon (1-3). Recently, we demonstrated this phenomenon directly in vivo in streptozotocin-induced diabetic rats and in vitro using isolated islets from these animals. In the in vivo studies, an insulin infusion into the pancreatic artery was switched off when the animals were made hypoglycemic by a jugular-vein infusion of insulin (4).Glucagon secretion, absent in control diabetic animals, was fully restored by this maneuver. Glucagon release was not initiated by this maneuver if saline rather than insulin was used, or if insulin was infused but not switched off. The glucagon response was not observed during normoglycemic or hyperglycemic conditions; the switch-off signal was effective only in the setting of hypoglycemia. We corroborated these findings with in vitro islet perifusion studies (5).Recent work from several laboratories has demonstrated that zinc atoms are capable of suppressing ␣-cell function via activation of rat ␣-cell ATP-sensitive K ϩ (K ATP ) channels (6 -9). Since zinc atoms are bound by and cosecreted with insulin, we hypothesized that zinc might provide the switch-off signal during hypoglycemia. To evaluate this hypothesis, we performed in vivo studies using intrapancreatic artery infusions of zinc-containing insulin, zinc chloride alone, or zinc-free insulin in streptozo...

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Regulation of α-Cell Function by the β-Cell During Hypoglycemia in Wistar Rats: the “Switch-off” Hypothesis

Cited by 97 publications

References 44 publications

Determinants of glucose control in patients with chronic pancreatitis

Determinants of glucose control in patients with chronic pancreatitis

Regulation of α-Cell Function by the β-Cell in Isolated Human and Rat Islets Deprived of Glucose: the “Switch-off” Hypothesis

Zinc, Not Insulin, Regulates the Rat α-Cell Response to Hypoglycemia In Vivo

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