Loss of the Decrement in Intraislet Insulin Plausibly Explains Loss of the Glucagon Response to Hypoglycemia in Insulin-Deficient Diabetes

Raju, Bharathi; Cryer, Philip E.

doi:10.2337/diabetes.54.3.757

Cited by 137 publications

(113 citation statements)

References 51 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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“…However, the contribution that this nerve loss (eSIN) makes to the impaired glucagon response to IIH in diabetic NOD mice remains to be established. In contrast, there is published evidence that the loss of islet beta cells does contribute to this impairment in diabetic humans [37] and in rat models of diabetes [6,38]; therefore, it is likely to contribute in the diabetic NOD mouse. We have not ruled out a generalised alpha cell defect in these cyclophosphamide-treated, 3 week diabetic NOD mice, due either to alpha cell loss or islet inflammation secondary to invasive insulitis.…”

Section: Discussionmentioning

confidence: 67%

Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

et al. 2009

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Aims/hypothesis We hypothesised that non-obese diabetic mice (NOD) mice have an autoimmune-mediated loss of islet sympathetic nerves and an impairment of sympathetically mediated glucagon responses. We aimed: (1) to determine whether diabetic NOD mice have an early impairment of the glucagon response to insulin-induced hypoglycaemia (IIH) and a coincident loss of islet sympathetic nerves; (2) to determine whether invasive insulitis is required for this nerve loss; and (3) to determine whether sympathetically mediated glucagon responses are also impaired. Methods We measured glucagon responses to both IIH and tyramine in anaesthetised mice. We used immunohistochemistry to quantify islet sympathetic nerves and invasive insulitis. Results The glucagon response to IIH was markedly impaired in NOD mice after only 3 weeks of diabetes (change, −70%). Sympathetic nerve area within the islet was also markedly reduced at this time (change, −66%). This islet nerve loss was proportional to the degree of invasive insulitis. More importantly, blocking the infiltration prevented the nerve loss. Mice with autoimmune diabetes had an impaired glucagon response to sympathetic nerve activation, whereas those with non-autoimmune diabetes did not. Conclusions/interpretation The invasive insulitis seen in diabetic NOD mice causes early sympathetic islet neuropathy. Further studies are needed to confirm that early sympathetic islet neuropathy is responsible for the impaired glucagon response to tyramine.

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“…The decrement in insulin release from ␤-cells has been proposed to signal the ␣-cell to release glucagon (1)(2)(3). Recently, we demonstrated this phenomenon directly in vivo in streptozotocin-induced diabetic rats and in vitro using isolated islets from these animals.…”

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confidence: 81%

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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Loss of the Decrement in Intraislet Insulin Plausibly Explains Loss of the Glucagon Response to Hypoglycemia in Insulin-Deficient Diabetes

Cited by 137 publications

References 51 publications

Determinants of glucose control in patients with chronic pancreatitis

Determinants of glucose control in patients with chronic pancreatitis

Loss of islet sympathetic nerves and impairment of glucagon secretion in the NOD mouse: relationship to invasive insulitis

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

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