Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects.

Palmer, Jerry P.; Benson, James W.; Walter, Robert M.; Ensinck, John W.

doi:10.1172/jci108502

Cited by 182 publications

(97 citation statements)

References 28 publications

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“…These diabetic rats exhibited a specific failure of insulin release in response to glucose coexisting with a relative preservation of the responses to other secretagogues [17]. Such a pattern resembles that shown in some studies of human Type 2 diabetes [18][19][20] and is also charcteristic of Type1 diabetes in the early stage of the disease [21] and of Type 2 diabetes of the young [22]. This study was designed to determine if short-term (1 day) or long-term (30 days) oral gliclazide treatment modifies the pancreatic insulin content and the in vitro B-cell response to secretagogues (glucose, arginine and gliclazide) using the isolated perfused pancreas technique.…”

supporting

confidence: 74%

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

1989

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Summary. Neonatal rats treated with streptozotocin on the day of birth (n0-STZ) or on day 5 (n5-STZ) exhibited when fully grown a very mild or frank basal hyperglycaemia respectively and a specific failure of insulin release in response to glucose. To determine whether short (1 day) or long-term (30 days) gliclazide treatment modifies the pancreatic insulin content and the B-cell response to secretagogues, diabetic rats were given oral gliclazide (10 mg/kg per day) and compared to control diabetic and non-diabetic rats. Insulin secretion in the isolated perfused pancreas was studied the day after the last gliclazide administration. In severely hyperglycaemic n5-STZ rats (plasma glucose levels > 16 mmol/1) long-term gliclazide treatment did not lower the plasma glucose values, did not affect the pancreatic insulin stores, nor did it significantly modify the insulin release in vitro in response to glucose or arginine. In moderately hyperglycaemic n5-STZ rats (plasma glucose levels <16retool/I) the plasma glucose levels declined progressively reaching 8 mmol/l as a mean at the end of the gliclazide therapy. In the n5-STZ rats responsive to gliclazide the pancreatic insulin stores were increased twofold as compared to values in untreated n5-STZ rats, however, this difference did not reached significance and the pancreatic insulin stores in the responsive gliclazide treated rats remained depleted by 76% compared to normal insulin stores. In the n0-STZ rats (very mild hyperglycaemia) the long-term gliclazide treatment did not significantly modify the plasma glucose levels or the pancreatic insulin stores. After the 30-day gliclazide therapy in both the n5-STZ gliclazide responder group and the n0-STZ group: (1) the in vitro glucose-induced insulin secretion was increased three to fivefold, (2) the response to arginine which was basically increased in the untreated diabetic rats was again amplified two to threefold, (3) the insulin release in resp, onse to gliclazide was unchanged. In conclusion, long-term gliclazide therapy augments stimulated insulin secretion in these two rat models of Type 2 (non-insulin-dependent) diabetes and does not induce any refractoriness to acute sulfonylurea stimulation. The improvement of Bcell function observed here was not related to the concomitant variations of hyperglycaemia and/or pancreatic insulin content

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supporting

confidence: 74%

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

1989

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“…CONCLUSIONS -The arginine stimulation test has been demonstrated to be a valid method for evaluating residual ␤-cell function, even during periods of hyperglycemia (3,4,(22)(23)(24). However, the relevance of the glucagon response to arginine remains uncertain and has not been comprehensively analyzed in patients with type 1 and type 2 diabetes.…”

Section: Resultsmentioning

confidence: 99%

Possible Role of α-Cell Insulin Resistance in Exaggerated Glucagon Responses to Arginine in Type 2 Diabetes

et al. 2007

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OBJECTIVE -Inappropriate excessive secretion of glucagon, which contributes to postprandial hyperglycemia, is a novel target for the treatment of diabetes. In this study, we sought to determine the factors associated with exaggerated glucagon secretion in response to an arginine challenge in patients with type 1 and type 2 diabetes.RESEARCH DESIGN AND METHODS -Changes in circulating C-peptide immunoreactivity (CPR) and immunoreactive glucagon (IRG) after an arginine challenge were investigated in 35 patients with type 1 diabetes, 130 patients with type 2 diabetes, and 35 nondiabetic control subjects.RESULTS -No significant differences were found in the basal level and the area under the concentration-time curve (AUC) of IRG (AUC IRG ) among type 1 and type 2 diabetic patients and nondiabetic subjects. However, there was an inverse correlation between the AUC IRG and the AUC of CPR (AUC CPR ) for type 1 (r ϭ Ϫ0.388, P ϭ 0.023) and type 2 (r ϭ 0.396, P Ͻ 0.0001) diabetic patients, whereas AUC IRG was not correlated with AUC CPR in nondiabetic subjects (r ϭ Ϫ0.079, P ϭ 0.655). In type 1 diabetic patients, the AUC CPR decreased and the AUC IRG increased with increasing disease duration. In type 2 diabetic patients, both AUC IRG and AUC CPR increased with increasing BMI, basal CPR level, and homeostasis model assessment of insulin resistance value.CONCLUSIONS -Our findings suggest that the pathophysiology of the exaggerated glucagon response differs between type 1 and type 2 diabetes. Intraislet insulin deficiency and ␣-cell insulin resistance may be the primary contributors to this condition in type 1 and type 2 diabetes, respectively. Diabetes Care 30:2583-2587, 2007D iabetes is associated with increased hepatic glucose production, which is linked to fasting and postprandial hyperglycemia (1). This is caused by the reduced suppression of glucagon (2), along with the impairment of insulin secretion and insulin action. Arginine-stimulated hyperglucagonemia in patients with various forms of diabetes was first discovered by Aronoff et al. (3,4). Their results demonstrated that excess glucagon or an elevated ratio of glucagon to insulin is etiologically important in the development of endogenous hyperglycemia in diabetes through the mediation of glucose overproduction from the liver (2,5-7). Thus, glucagon and its receptor have been examined extensively in recent years as being potential targets for the treatment of diabetes (8,9). In fact, glucagon-like peptide 1 analogs, which are forthcoming antidiabetes agents, lower postprandial hyperglycemia partly by inhibiting excessive secretion of glucagon in not only type 2 but also type 1 diabetes (10). An absolute deficiency in insulin secretion has been suggested to cause an exaggerated response of glucagon to arginine in patients with diabetes (11,12). Insulin replacement therapy can correct this deficiency in patients with type 1 diabetes (11,12) but not in those with type 2 diabetes (11). The pathophysiology associated with an exaggerated glucagon response to arginine r...

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“…It has long been recognized that NO is a potent secretagogue for b-cell insulin release (Palmer et al 1976), BRIN-BD11 cells (1 . 5!10 6 per well) were prepared, cultivated, and electrophoretically analyzed as described in the legend of Fig.…”

Section: Discussionmentioning

confidence: 99%

Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets

Krause¹,

Bittencourt²,

Bittencourt³

et al. 2012

Journal of Endocrinology

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Interleukin-6 (IL6) has recently been reported to promote insulin secretion in a glucagon-like peptide-1-dependent manner. Herein, the direct effects of IL6 (at various concentrations from 0 to 1000 pg/ml) on pancreatic b-cell metabolism, AMP-activated protein kinase (AMPK) signaling, insulin secretion, nitrite release, and redox status in a rat clonal b-cell line and mouse islets are reported. Chronic insulin secretion (in mg/mg protein per 24 h) was increased from 128 . 7G7 . 3 (no IL6) to 178 . 4G7 . 7 (at 100 pg/ml IL6) in clonal b-cells and increased significantly in islets incubated in the presence of 5 . 5 mM glucose for 2 h, from 0 . 148 to 0 . 167G0 . 003 ng/islet. Pretreatment with IL6 also induced a twofold increase in basal and nutrientstimulated insulin secretion in subsequent 20 min static incubations. IL6 enhanced both glutathione (GSH) and glutathione disulphide (GSSG) by nearly 20% without changing intracellular redox status (GSSG/GSH). IL6 dramatically increased iNOS expression (by ca. 100-fold) with an accompanying tenfold rise in nitrite release in clonal b-cells. Phosphorylated AMPK levels were elevated approximately twofold in clonal b-cells and mouse islet cells. Calmodulin-dependent protein kinase kinase levels (CaMKK), an upstream kinase activator of AMPK, were also increased by 50% after IL6 exposure (in b-cells and islets). Our data have demonstrated that IL6 can stimulate b-cell-dependent insulin secretion via direct cell-based mechanisms. AMPK, CaMKK (an upstream kinase activator of AMPK), and the synthesis of nitric oxide appear to alter cell metabolism to benefit insulin secretion. In summary, IL6 exerts positive effects on b-cell signaling, metabolism, antioxidant status, and insulin secretion.

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Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects.

Cited by 182 publications

References 28 publications

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

Long-term gliclazide treatment improves the in vitro glucose-induced insulin release in rats with Type 2 (non-insulin-dependent) diabetes induced by neonatal streptozotocin

Possible Role of α-Cell Insulin Resistance in Exaggerated Glucagon Responses to Arginine in Type 2 Diabetes

Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets

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