Biomedical subjects
D Maggs
Publications and source records attributed to D Maggs.
Effect of pramlintide on A1C and body weight in insulin-treated African Americans and Hispanics with type 2 diabetes: a pooled post hoc analysis.
An unresolved problem in the management of type 2 diabetes is that improvement of glycemic control with insulin, insulin secretagogues, and insulin sensitizers is often accompanied by undesired weight gain. This problem is of particular concern in ethnic groups with a high propensity for diabetes and obesity, such as African Americans and Hispanics. Two 1-year, randomized, double-blind, placebo-controlled clinical trials in insulin-treated patients with type 2 diabetes have shown that adjunctive therapy with pramlintide, an analog of the human beta-cell hormone amylin, reduces A(1C) with concomitant weight loss, rather than weight gain. To assess the effect of pramlintide in various ethnic groups with type 2 diabetes using insulin, we conducted a pooled post hoc analysis of the 2 trials, which included all Caucasian (n = 315), African American (n = 47), and Hispanic (n = 48) patients (age 57 years, A(1C) 9.1%, body mass index [BMI] 33 kg/m(2), mean values) who completed 52 weeks of treatment with either pramlintide (120 microg twice daily or 150 microg 3 times a day) or placebo. Primary endpoints included changes from baseline to week 52 in A(1C) and body weight. Collectively, pramlintide-treated patients achieved significant reductions from baseline in both A(1C) and body weight (placebo-corrected treatment effects at week 52: -0.5% and -2.6 kg, respectively, both P <.0001). The simultaneous reduction in A(1C) and body weight at week 52 was evident across all 3 ethnic groups and appeared to be most pronounced in African Americans (-0.7%, -4.1 kg), followed by Caucasians (-0.5%, -2.4 kg) and Hispanics (-0.3%, -2.3 kg). The glycemic improvement with pramlintide was not associated with an increased incidence of hypoglycemia over the entire study period (43% pramlintide v 40% placebo). Nausea, the most common adverse event associated with pramlintide treatment, was mostly mild and confined to the first 4 weeks of therapy (25% pramlintide v 16% placebo) with comparable patterns in the 3 ethnic groups. Thus, pending further experience, the combined improvement in glycemic and weight control with pramlintide treatment appears to be generalizable to a broad population of mixed ethnicity.
Addition of pramlintide to insulin therapy lowers HbA1c in conjunction with weight loss in patients with type 2 diabetes approaching glycaemic targets.
AIM: Two long-term, randomized, double-blind, placebo-controlled clinical trials in insulin-using patients with type 2 diabetes, spanning a wide range of baseline glycaemic control, have shown that the addition of pramlintide, an analogue of the beta-cell hormone amylin, to pre-existing insulin regimens results in reductions in HbA1c that are accompanied by weight loss. METHODS: To assess whether this profile of pramlintide is observed in patients approaching, but not yet reaching, glycaemic targets, we conducted a pooled post hoc analysis of the two trials, including all patients with an entry HbA1c between 7.0 and 8.5%. Within this subset of patients, 80 were treated with placebo + insulin [baseline HbA1c 8.0 +/- 0.3%, weight 87.3 +/- 19.3 kg (mean +/- s.d.)] and 86 with pramlintide (120 micro g bid) + insulin [HbA1c 8.0 +/- 0.4%, weight 92.5 +/- 20.4 kg (mean +/- s.d.)]. Endpoints included changes from baseline to Week 26 in HbA1c, body weight, and the event rate of severe hypoglycaemia. RESULTS: Adjunctive therapy with pramlintide resulted in significant reductions in both HbA1c and body weight from baseline to Week 26 (-0.43% and -2.0 kg differences from placebo, respectively, both p < 0.001). These changes were achieved without a concomitant increase in the overall rate of severe hypoglycaemic events (0.13 pramlintide vs. 0.19 placebo, events/patient year of exposure). CONCLUSIONS: The data from this post hoc analysis indicate that the addition of pramlintide to insulin therapy may help patients with type 2 diabetes who are approaching, but not yet reaching, glycaemic targets to achieve further reductions in HbA1c without concomitant weight gain and increased risk of severe hypoglycaemia.
Pathogenesis of herpes simplex virus type 1-induced corneal inflammation in perforin-deficient mice.
Herpetic stromal keratitis (HSK) is an inflammatory disease of the cornea that often results in blindness. It is mediated by a host immune response which is triggered by herpes simplex virus (HSV) infection. Immune effector mechanisms are hypothesized to be important in disease development. We investigated, in a mouse model, whether perforin-dependent cytotoxicity is an important effector mechanism in the production of HSK. Wild-type (C57BL/6) and perforin-deficient (PKO) mice were infected intracorneally with HSV-1 strain F. Clinical disease and histologic lesions of the cornea at 23 days postinfection (p.i.) were significantly less severe in HSV-1-infected PKO mice than in infected wild-type mice. mRNA for the chemokine macrophage inflammatory protein 1alpha (MIP-1alpha) was detected by reverse transcription-PCR in the corneas of infected wild-type mice but not in the corneas of infected PKO mice at 23 days p.i. Adoptive transfer of wild-type HSV-1 immune T-cell-enriched splenocytes into HSV-1-infected PKO mice restored the disease phenotype which was seen in infected wild-type mice. In contrast, mice carrying a null-function mutation in the Fas ligand, which is involved in an alternative cytotoxic mechanism, developed clinical disease and histologic lesions which were comparable to those in wild-type mice. Viral clearance from the eyes of PKO mice was not impaired. There was no significant difference between the infectious viral titers isolated from the eyes of PKO and wild-type mice. Our findings show that perforin is important in the pathogenesis of HSK.
The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity.
Although low GH levels are commonly seen in obese adults and children, the effects of obesity on the insulin-like growth factor (IGF)/IGF-binding protein (IGFBP) system have not been established. As GH and IGF-I normally increase during adolescence, we investigated the effects of obesity on circulating total and free IGF-I levels and IGFBP-1, -2, and -3 in 19 obese adolescents [14 +/- 1 yr old; body mass index (BMI), 34 +/- 3], 20 lean adolescents (14 +/- 1 yr old; BMI, 23 +/- 0.5), and 10 lean adults (22 +/- 0.7 yr; BMI, 22 +/- 0.7). Fasting plasma insulin levels were significantly greater in obese adolescents than in either lean group, whereas circulating IGFBP-1 levels were suppressed in an inverse relationship to basal insulin (r = -0.49; P < 0.01). Low IGFBP-1 levels were associated with normal to increased free IGF-I levels in obese adolescents, even though total IGF-I values were lower than those in lean adolescents. Basal GH and IGFBP-3 levels were also lower in obese vs. lean adolescents. Basal IGFBP-1 levels were markedly reduced in obese adolescents (14 +/- 3 ng/mL) vs. those in adolescents and adults. No further suppression of IGFBP-1 levels was observed in the obese group during a two-step 8 and 40 mU/m2 insulin clamp. In contrast, IGFBP-1 levels were promptly lowered in lean adults. Basal IGFBP-2 levels were significantly lower in both groups of adolescents vs. lean adults (P < 0.05), and IGFBP-2 levels did not change during euglycemic hyperinsulinemia. These data suggest that the compensatory hyperinsulinemia that characterizes adolescent obesity chronically suppresses levels of IGFBP-1, and low IGFBP-1 concentrations may serve to increase the bioavailability of free IGF-I, which may, in turn, contribute to lower circulating GH, total IGF-I, and IGFBP-3 concentrations.
Can hypoglycaemia be predicted before its onset?
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Hyperleptinemia: an early sign of juvenile obesity. Relations to body fat depots and insulin concentrations.
Leptin, the OB gene product, is an adipocyte-derived circulating protein. In several rodent models of obesity, such as the db/db mice, fa/fa rats, and ventromedial hypothalamus-lesioned mice, as well as adult obese subjects, leptin mRNA expression and the circulating levels are elevated, suggesting resistance to its action. However, it is unknown whether the rise in leptin concentration occurs early in the natural evolution of human obesity or is a chronic adaptation to the obese state. Moreover, whether the distribution of body fat (i.e., visceral vs. subcutaneous abdominal fat) influences circulating leptin levels has not been assessed. We have determined in a group of obese and nonobese children and young adults whether leptin levels 1) are increased early in the development of obesity, 2) are related to a specific fat depot measured by magnetic resonance imaging, 3) vary during hyperinsulinemic, euglycemic, and hyperglycemic clamp studies, and 4) are different in males vs. females. In the basal state, leptin levels were elevated in obese children. Children and adults demonstrated a strong positive correlation between leptin concentrations and the subcutaneous fat depot (r = 0.84, P < 0.001). Surprisingly, a weaker correlation was found with visceral fat mass (r = 0.59, P = 0.001). Leptin levels remained unchanged under both euglycemic and hyperglycemic hyperinsulinemic conditions in both obese and nonobese subjects. A pronounced effect of gender on leptin levels was also observed. We conclude that, early in the development of juvenile obesity, leptin concentrations are elevated and are more closely linked to subcutaneous than visceral fat mass. Acute increases in insulin concentrations do not affect circulating leptin levels.