Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.

Ward, W. Kenneth; Bolgiano, Doug; McKnight, Barbara; Halter, Jeffrey B.; Porte, Daniel

doi:10.1172/jci111542

Cited by 478 publications

(392 citation statements)

References 29 publications

Supporting

Mentioning

374

Contrasting

Unclassified

Order By: Relevance

“…The glucose-dependent arginine-stimulation test was initially developed for the careful analysis of beta cell function, since it displays both basal and maximal insulin secretion as well as glucose sensitivity of the beta cells [15,16]. However, since arginine stimulates glucagon secretion as well, and since glucose suppresses alpha cell secretion, the test is also useful for characterising alpha cell function.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Åhrén

2005

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis: The study evaluated whether glucagon secretion is regulated by changes in insulin sensitivity under normal conditions. Materials and methods: A total of 155 healthy women with NGT (aged 53-70 years) underwent a glucose-dependent arginine-stimulation test for evaluation of glucagon secretion. Arginine (5 g) was injected i.v. under fasting conditions (plasma glucose 4.8±0.1 mmol/l) and after raising blood glucose concentrations to 14.8±0.1 and 29.8±0.2 mmol/l. The acute glucagon response (AGR) to arginine during the three glucose levels (AGR 1 , AGR 2 , AGR 3 ) was estimated, as was the suppression of baseline glucagon by the increased glucose. All women also underwent a 2-h euglycaemic-hyperinsulinaemic clamp study for estimation of insulin sensitivity. Results: Insulin sensitivity was normally distributed, with a mean of 73.2±29.3 (SD) nmol glucose kg −1 min −1 /pmol insulin l −1 . When relating the variables obtained from the arginine test to insulin sensitivity, insulin resistance was associated with increased AGR and with increased suppression of glucagon levels by glucose. For example, the regression between insulin sensitivity and AGR 2 was r=−0.38 (p<0.001) and between insulin sensitivity and suppression of glucagon levels by 14.8 mmol/l glucose r=0.36 (p<0.001). Insulin sensitivity also correlated negatively with insulin secretion; multivariate analysis revealed that changes in insulin sensitivity and insulin secretion were independently related to changes in glucagon secretion. Conclusions/ interpretation: The body adapts to insulin resistance by increasing the glucagon response to arginine and by increasing the suppression of glucagon levels by glucose. Hence, not only the islet beta cells but also the alpha cells seem to undergo compensatory changes during the development of insulin resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

“…arginine stimulation at three glucose levels (fasting, 14 and >25 mmol/l) as previously described [15,16]. After an overnight fast, i.v.…”

Section: Methodsmentioning

confidence: 99%

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Åhrén

2005

Diabetologia

View full text Add to dashboard Cite

show abstract

“…Glucose-dependent arginine stimulation test and trimethaphan infusions Insulin secretion was determined with intravenous arginine stimulation at three glucose levels (fasting, 13-15 and >28 mmol/l) as previously described [23,24]. After an overnight fast, intravenous catheters were inserted into antecubital veins in both arms.…”

Section: Methodsmentioning

confidence: 99%

“…Trimethaphan impairs neurotransmission across the autonomic ganglia and in the adrenal medulla [20] and has been used previously to evaluate autonomic regulation of islet function [21,22]. The glucose-dependent argininestimulation test, which allows for estimation of baseline as well as glucose-augmented and maximal insulin secretion, has also been used in previous studies [23,24]. Finally, short-term dexamethasone treatment has previously been shown to be a model for inducing insulin resistance in humans [8,25].…”

Section: Introductionmentioning

confidence: 99%

Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans

Åhrén

2008

Diabetologia

View full text Add to dashboard Cite

Aims/hypothesis This study examined whether autonomic mechanisms contribute to adaptively increased insulin secretion in insulin-resistant humans, as has been proposed from studies in animals. Methods Insulin secretion was evaluated before and after induction of insulin resistance with or without interruption of neural transmission. Insulin resistance was induced by dexamethasone (15 mg given over 3 days) in nine healthy women (age 67 years, BMI 25.2±3.4 kg/m 2 , fasting glucose 5.1± 0.4 mmol/l, fasting insulin 46±6 pmol/l). Insulin secretion was evaluated as the insulin response to intravenous arginine (5 g) injected at fasting glucose and after raising glucose to 13 to15 mmol/l or to >28 mmol/l. Neural transmission across the ganglia was interrupted by infusion of trimethaphan (0.3-0.6 mg kg −1 min −1 ). Results As an indication of insulin resistance, dexamethasone increased fasting insulin (to 75±8 pmol/l, p<0.001) without significantly affecting fasting glucose. Arginine-induced insulin secretion was increased by dexamethasone at all glucose levels (by 64±12% at fasting glucose, by 80± 19% at 13-15 mmol glucose and by 43±12% at >28 mmol glucose; p<0.001 for all). During dexamethasone-induced insulin resistance, trimethaphan reduced the insulin response to arginine at all three glucose levels. The augmentation of the arginine-induced insulin responses by dexamethasoneinduced insulin resistance was reduced by trimethaphan by 48±6% at fasting glucose, 61±8% at 13-15 mmol/l glucose and 62±8% at >28 mmol/l glucose (p<0.001 for all). In contrast, trimethaphan did not affect insulin secretion before dexamethasone was given. Conclusions/interpretations Autonomic mechanisms contribute to the adaptative increase in insulin secretion in dexamethasone-induced insulin resistance in healthy participants.

show abstract

“…The minimum AGR arg (seen at plasma glucose levels above ∼25 mmol/l in healthy subjects [29]) and the slope of the linear portion of the curve provide information on the responsiveness of the alpha cell to glucose-induced suppression, and the PG 50 , the glucose level at which halfmaximal suppression occurs, is a measure of alpha cell sensitivity to glucose. It should be noted that the PG 50 may be underestimated if a minimum AGR arg is not achieved at the highest glucose level tested.…”

Section: Clinical Measures Of Alpha Cell Functionmentioning

confidence: 99%

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Dunning¹,

2005

View full text Add to dashboard Cite

Although there is abundant evidence that hyperglucagonaemia plays a key role in the development of hyperglycaemia in type 2 diabetes, efforts to understand and correct this abnormality have been overshadowed by the emphasis on insulin secretion and action. However, recognition that the incretin hormone glucagon-like peptide-1 (GLP-1) exerts opposing effects on glucagon and insulin secretion has revived interest in glucagon, the neglected partner of insulin, in the bihormonal hypothesis. In healthy subjects, glucagon secretion is regulated by a variety of nutrient, neural and hormonal factors, the most important of which is glucose. The defect in alpha cell function that occurs in type 2 diabetes reflects impaired glucose sensing. GLP-1 inhibits glucagon secretion in vitro and in vivo in experimental animals, and suppresses glucagon release in a glucose-dependent manner in healthy subjects. This effect is also evident in diabetic patients, but GLP-1 does not inhibit glucagon release in response to hypoglycaemia, and may even enhance it. Early clinical studies with agents acting through GLP-1 signalling mechanisms (e.g. exenatide, liraglutide and vildagliptin) suggest that GLP-1 can improve alpha cell glucose sensing in patients with type 2 diabetes. Therapeutic approaches based around GLP-1 have the potential to improve both alpha cell and beta cell function, and could be of benefit in patients with a broad range of metabolic disorders.

show abstract

Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.

Cited by 478 publications

References 29 publications

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Glucagon secretion in relation to insulin sensitivity in healthy subjects

Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans

Alpha cell function in health and disease: influence of glucagon-like peptide-1

Contact Info

Product

Resources

About