The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus

Nyholm, Birgit; Ørskov, L.; Hove, Karen Yde; Gravholt, Claus Højbjerg; Møller, Niels; George, K.; Alberti, M.M.; Moyses, Chris; Kolterman, Orville G.; Schmitz, Ole

doi:10.1016/s0026-0495(99)90232-9

Cited by 97 publications

(87 citation statements)

References 31 publications

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“…Alternatively, the insulinmediated suppression of ␣-cell secretion may be abnormal either because of lower intra-islet insulin levels or because the autoimmune milieu attenuates the paracrine effects of the secreted insulin. Although elevations in plasma glucagon do not have a measurable effect on postprandial glycemia in healthy humans (26), the contribution of abnormal glucagon suppression to glucose intolerance in diabetic subjects has been reported (27)(28)(29). We do not think the persistence of basal glucagon levels during the OGTT is likely to be the primary factor in the postprandial glycemic pattern in our type 1 diabetic subjects.…”

Section: Discussionmentioning

confidence: 62%

“…We do not think the persistence of basal glucagon levels during the OGTT is likely to be the primary factor in the postprandial glycemic pattern in our type 1 diabetic subjects. However, as previously suggested (27)(28)(29), it is reasonable to believe that the relative hyperglucagonemia during the OGTT in the type 1 diabetic group contributes to their hyperglycemia, probably through persistent stimulation of hepatic glucose production.…”

Section: Discussionmentioning

confidence: 76%

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Impaired β-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose

Greenbaum¹,

Prigeon

D’Alessio

2002

Diabetes

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We have recently described a novel phenotype in a group of subjects with type 1 diabetes that is manifested by glucose >11.1 mmol/l 120 min after an oral glucose load, but with normal fasting glucose levels. We now describe the metabolic characteristics of these subjects by comparing parameters of islet hormone secretion and glucose disposal in these subjects to age-matched nondiabetic control subjects. The patients with type 1 diabetes had fasting glucose, insulin, and glucagon values similar to those of control subjects. Additionally, the insulin secretory response to intravenous arginine at euglycemia was similar in the control and diabetic groups (264 ؎ 33.5 and 193 ؎ 61.3 pmol/l; P ‫؍‬ 0.3). However, marked differences in ␤-cell function were found in response to hyperglycemia. Specifically, the first-phase insulin response was lower in diabetic subjects (329.1 ؎ 39.6 vs. 91.3 ؎ 34.1 pmol/l; P < 0.001), as was the slope of glucose potentiation of the insulin response to arginine (102 ؎ 18.7 vs. 30.2 ؎ 6.1 pmol/l per mmol/l; P ‫؍‬ 0.005) and the maximum insulin response to arginine (2,524 ؎ 413 vs. 629 ؎ 159 pmol/l; P ‫؍‬ 0.001). Although plasma levels of glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) did not differ between control and diabetic subjects, the incretin effect was lower in the diabetic patients (70.3 ؎ 5.4 vs. 52.1 ؎ 5.9%; P ‫؍‬ 0.03). Finally, there was a lack of suppression of glucagon in the patients after both oral and intravenous glucose administration, which may have contributed to their postprandial hyperglycemia. Glucose effectiveness did not differ between patients and control subjects, nor did insulin sensitivity, although there was a tendency for the patients to be insulin resistant (9.18 ؎ 1.59 vs. 5.22 ؎ 1.17 pmol ⅐ l -1 ⅐ min -1 ; P ‫؍‬ 0.08). These data characterize a novel group of subjects with type 1 diabetes manifested solely by hyperglycemia following an oral glucose load in whom islet function is normal at euglycemia, but who have marked defects in both ␣-and ␤-cell secretion at hyperglycemia. This pattern of abnormalities may be characteristic of islet dysfunction early in the development of type 1 diabetes. Diabetes 51:951-957, 2002

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 76%

Impaired β-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose

Greenbaum¹,

Prigeon

D’Alessio

2002

Diabetes

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“…First, a slowing of the rate of nutrient delivery from the stomach to the small intestine was demonstrated (15,16). Second, prevention of an abnormal postprandial increase in plasma glucagon was demonstrated (17,18). Consequently, a marked improvement in postprandial glucose excursions was seen (17,19).…”

mentioning

confidence: 99%

“…Second, prevention of an abnormal postprandial increase in plasma glucagon was demonstrated (17,18). Consequently, a marked improvement in postprandial glucose excursions was seen (17,19).…”

mentioning

confidence: 99%

A Randomized Study and Open-Label Extension Evaluating the Long-Term Efficacy of Pramlintide as an Adjunct to Insulin Therapy in Type 1 Diabetes

Whitehouse

Kruger²,

Fineman³

et al. 2002

Diabetes Care

248

253

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OBJECTIVE -To assess the effect of mealtime amylin replacement with pramlintide on long-term glycemic and weight control in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS-In a 52-week, double-blind, placebocontrolled, multicenter study, 480 patients with type 1 diabetes were randomized to receive preprandial injections of placebo or 30 g pramlintide q.i.d., in addition to existing insulin regimens. At week 20, pramlintide-treated patients were re-randomized to 30 or 60 g pramlintide q.i.d. if decreases from baseline in HbA 1c were Ͻ1% at week 13. Of the 342 patients who completed the 52-week study, 236 individuals (ϳ70%) elected to participate in a 1-year openlabel extension in which all patients received 30 or 60 g pramlintide q.i.d..RESULTS -Treatment with pramlintide led to a mean reduction in HbA 1c of 0.67% from baseline to week 13 that was significantly (P Ͻ 0.0001) greater than the placebo reduction (0.16%), and a significant placebo-corrected treatment difference was sustained through week 52 (P ϭ 0.0071). The greater HbA 1c reduction was associated with an average weight loss, rather than weight gain, and was not accompanied by an increased overall event rate of severe hypoglycemia. In the open-label extension, mean HbA 1c levels decreased rapidly in patients receiving pramlintide for the first time and remained at reduced levels in patients who continued pramlintide treatment. The most common adverse events reported by the pramlintide group were mild nausea and anorexia, which both occurred during the initial weeks of treatment and dissipated over time.CONCLUSIONS -Mealtime pramlintide treatment as an adjunct to insulin improved longterm glycemic control without inducing weight gain or increasing the overall risk of severe hypoglycemia in patients with type 1 diabetes. Diabetes Care 25:724 -730, 2002

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“…To overcome this, a soluble, non-aggregating, equipotent analog of human amylin, pramlintide, was formulated ( Figure 2 Clinical evaluations of pramlintide have shown reductions in postprandial glucose concentrations through at least three distinct mechanisms of action, including slowing of gastric emptying, prevention of the postprandial rise in plasma glucagon, and increased satiety, leading to decreased caloric intake and potential weight loss. [12][13][14][15][16][17] Patients with diabetes often exhibit accelerated gastric emptying compared to healthy individuals. 18 This may be a result of deficient amylin secretion in response to meals, among other factors.…”

Section: Pramlintide: Mechanism Of Actionmentioning

confidence: 99%

Pramlintide: Clinical Strategies for Success

Alrefai¹,

Latif²,

Hieronymus³

et al. 2010

Diabetes Spectrum

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The amylin analog pramlintide improves glycemic control and reduces postprandial glucagon concentrations in patients with type 1 diabetes mellitus

Cited by 97 publications

References 31 publications

Impaired β-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose

Impaired β-Cell Function, Incretin Effect, and Glucagon Suppression in Patients With Type 1 Diabetes Who Have Normal Fasting Glucose

A Randomized Study and Open-Label Extension Evaluating the Long-Term Efficacy of Pramlintide as an Adjunct to Insulin Therapy in Type 1 Diabetes

Pramlintide: Clinical Strategies for Success

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