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Graydon S Meneilly

Publications and source records attributed to Graydon S Meneilly.

16 recordsLinked to original sources
PubMed2007

Effect of exenatide on beta cell function after islet transplantation in type 1 diabetes.

BACKGROUND: Islet transplantation can reduce or eliminate the need for insulin in patients with type 1 diabetes. Exenatide is a long acting analogue of Glucagon-like peptide-1 (GLP-1) that augments glucose induced insulin secretion, and may increase beta cell mass. We evaluated the effect of exenatide on insulin secretion after islet transplantation. METHODS: Eleven C-peptide positive islet cell recipients with elevated glucose levels were treated with exenatide for three months. Response was assessed by insulin requirements, meal tolerance tests, and hyperglycemic glucose clamps. RESULTS: Ten patients responded to exenatide. Two patients who had not restarted insulin achieved good glycemic control and one patient who had received 5500 IE/kg in first islet infusion was able to stop insulin. Seven other patients decreased their insulin dose by 39% on exenatide. Hyperglycemic clamp studies showed a rise in second phase insulin release (before exenatide: 246+/-88 pM; during exenatide: 644+/-294 pM, P<0.01). Meal tolerance studies before and one month after stopping exenatide did not show a difference in glucose or C-peptide values. Nausea and vomiting were the major side effects. CONCLUSIONS: Exenatide stimulates insulin secretion in islet transplant recipients. It reduces insulin dose in some patients and may delay the need to resume insulin in others. We did not find any evidence of a trophic effect on islets.

Adult↗
PubMed2006

Regulation of appetite in lean and obese adolescents after exercise: role of acylated and desacyl ghrelin.

CONTEXT: Increased physical activity is an integral part of weight loss programs in adolescents. We hypothesized that exercise could affect appetite-regulating hormones and the subjective desire to eat, which could partly explain the poor success rate of the existing interventions. OBJECTIVE: The objective of this study was to investigate prospectively the effects of exercise on acylated ghrelin (AG) and desacyl ghrelin (DG) concentrations and on appetite. SETTING: The setting for this study was a tertiary care center. PARTICIPANTS: Normal-weight [NW; body mass index (mean +/- se), 20.7 +/- 0.5 kg/m2] and overweight (OW; body mass index, 32.4 +/- 1.7) male adolescents (n = 17/group, age 15.3 +/- 0.2 yr) were studied. INTERVENTION: Those studied participated in 5 consecutive days of aerobic exercise (1 h/d). MAIN OUTCOME: Changes in AG and DG concentrations and in appetite during a test meal were studied. RESULTS: Exercise did not significantly affect insulin sensitivity or body weight. Fasting total (AG and DG) ghrelin concentrations were lower in OW (600 +/- 33 pg/ml) compared with NW (764 +/- 33 pg/ml, P < 0.05) boys and were not affected by exercise. In contrast, there was a differential effect of exercise on both AG and DG (P <or= 0.019). AG significantly increased after exercise, and this increase was greater in NW compared with OW adolescents (P < 0.05). Higher AG concentrations were correlated with an increase in markers of appetite (P < 0.05). CONCLUSION: Exercise differentially affects AG and DG in NW and OW male adolescents. Our data suggest that total ghrelin does not adequately reflect AG and DG concentrations and that the influence of exercise-induced hormonal changes should be considered to ensure success in weight management.

Acylation↗
PubMed2006

Pulsatile insulin secretion in elderly patients with diabetes.

Insulin pulsation is impaired in type 2 diabetes. GLP-1 increases pulsatile insulin secretion in these patients. We conducted these studies with the hypothesis that GLP-1 would enhance pulsatile insulin secretion and alter glucose metabolism in elderly patients with type 2 diabetes. Experiments were conducted in nine patients (age: 72+/-5 years; BMI: 27+/-3kg/m(2); diabetes duration: 7+/-3 years; HbA(1c): 6.6+/-0.9%). Subjects underwent three glucose clamp studies. The first was a euglycemic clamp to determine individual insulin clearance. In the second, GLP-1 was infused from 0-240min (0.75pM/kg/min) and glucose was maintained at fasting levels. The third was similar except that octreotide (30ng/kg/min) was infused with GLP-1 to suppress pulsatile insulin. Insulin and glucose were given to match levels during the second study. 3-(3)H-glucose was infused to allow calculation of hepatic glucose production and glucose disposal rates. There was no significant difference in measurements of pulsatile insulin secretion or hepatic glucose production and glucose disposal rates between the studies. Because there was no difference in pulsatile insulin between experiments, we could not test the effect of pulsatile insulin on glucose metabolism. Further studies are required to determine the impact of insulin pulses on glucose metabolism.

Aged↗
PubMed2006

Effect of glucagon-like peptide-1 (7-37) on beta-cell function after islet transplantation in type 1 diabetes.

Islet transplantation can improve glycemic control in patients with type 1 diabetes and reduce or eliminate the need for insulin. Glucagon-like peptide-1 (GLP-1) is an intestinal insulinotropic hormone that augments glucose induced insulin secretion, and has a trophic effect on beta-cells. We evaluated the effect of GLP-1 on insulin secretion after islet transplantation. Patients underwent hyperglycemic glucose clamp studies 1 month after their last transplant. GLP-1 was infused during the second hour of the hyperglycemic clamp. Results were compared to normal control subjects and patients with type 2 diabetes who underwent an identical hyperglycemic clamp. First phase insulin release was absent in patients, while second phase insulin was not significantly reduced (control: 118+/-29 pM; type 2 diabetes: 68+/-20 pM; transplant: 99+/-18 pM, p=ns for all). GLP-1 had a significant incretin effect on transplanted islets but the response was less than controls (control: 2108+/-344 pM; type 2 diabetes: 929+/-331 pM; transplant: 329+/-112 pM, p<0.0001 control versus transplant). Islet transplant patients had no evidence of resistance to insulin mediated glucose disposal. We conclude that transplanted islets retain the ability to respond to GLP-1.

Adult↗
PubMed2006

Diabetes in the elderly.

We are approaching an epidemic of diabetes in the elderly. This epidemic and its associated complications will have a significant impact on quality of life in this age group. Recent studies suggest that diabetes can be prevented in a large number of patients with appropriate interventions. It seems that diabetes in this age group is metabolically distinct. As a result, the approach to therapy in the elderly differs from that in younger patients. Unfortunately, we still have huge gaps in our understanding of the pathogenesis and treatment of diabetes in the aged, and further studies are needed urgently.

Age Factors↗
PubMed2005

Deconvolution analysis of rapid insulin pulses before and after six weeks of continuous subcutaneous administration of glucagon-like peptide-1 in elderly patients with type 2 diabetes.

CONTEXT: Insulin is secreted in a pulsatile fashion with measurable orderliness (low entropy). Normal aging and diabetes in middle-aged patients is characterized by alterations in pulsatile insulin release. OBJECTIVES: We undertook the current studies to determine whether disruptions in pulsatile insulin release also accompany diabetes in the elderly. DESIGN: Two studies were performed. In the first study, insulin values were sampled every minute for 1 h under fasting conditions. In the second study, subjects underwent a 2-h hyperglycemic glucose clamp (glucose 5.4 mm above basal). From 60-120 min, insulin was sampled every 1 min. Secretory pulse analysis was conducted using a multiparameter deconvolution technique. SETTING: The study was conducted in a general clinical research center and during outpatient visits. PATIENTS: Volunteers were healthy young [n = 10; body mass index (BMI), 23 +/- 1 kg/m2; age, 23 +/- 1 yr] and elderly (n = 10; BMI, 24 +/- 1 kg/m2; age, 78 +/- 2 yr) volunteers and elderly patients with diabetes (n = 8; BMI, 28 +/- 1 kg/m2; age, 73 +/- 2 yr). INTERVENTION: Five of the older patients with type 2 diabetes (BMI, 29 +/- 1 kg/m2; age, 72 +/- 2 yr) were treated with continuous sc glucagon-like peptide-1 (GLP-1) (7-36) amide infusion for 6 wk, and a second 2-h hyperglycemic clamp was performed. MAIN OUTCOME MEASURES: Insulin burst mass, pulsatile insulin secretion, and entropy were measured. RESULTS: Under fasting conditions, elderly patients with diabetes had a reduction in insulin burst mass (P < 0.05) that was similar to normal elderly. During hyperglycemia, elderly patients with diabetes had an even greater impairment in insulin burst mass (P < 0.05) and basal (P < 0.05) and pulsatile insulin secretion (P < 0.05) than normal elderly. Approximate entropy, a measure of irregularity of insulin release, was increased to a greater extent in older diabetes patients than normal elderly, signifying loss of orderliness of insulin secretion (P < 0.05). In response to treatment with GLP-1, insulin burst mass (P < 0.05) and pulsatile insulin secretion (P < 0.05) improved significantly in elderly patients with diabetes. CONCLUSIONS: We conclude that alterations in pulsatile insulin release can be improved in elderly patients with diabetes by the administration of sc GLP-1.

Adult↗
PubMed2003

Effects of 3 months of continuous subcutaneous administration of glucagon-like peptide 1 in elderly patients with type 2 diabetes.

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) is an insulinotropic gut hormone that, when given exogenously, may be a useful agent in the treatment of type 2 diabetes. We conducted a 3-month trial to determine the efficacy and safety of GLP-1 in elderly diabetic patients. RESEARCH DESIGN AND METHODS: A total of 16 patients with type 2 diabetes who were being treated with oral hypoglycemic agents were enrolled. Eight patients (aged 75 +/- 2 years, BMI 27 +/- 1 kg/m(2)) remained on usual glucose-lowering therapy and eight patients (aged 73 +/- 1 years, BMI 27 +/- 1 kg/m(2)), after discontinuing hypoglycemic medications, received GLP-1 delivered by continuous subcutaneous infusion for 12 weeks. The maximum dose was 120 pmol x kg(-1). h(-1). Patients recorded their capillary blood glucose (CBG) levels (four times per day, 3 days per week) and whenever they perceived hypoglycemic symptoms. The primary end points were HbA(1c) and CBG determinations. Additionally, changes in beta-cell sensitivity to glucose, peripheral tissue sensitivity to insulin, and changes in plasma ghrelin levels were examined. RESULTS: HbA(1c) levels (7.1%) and body weight were equally maintained in both groups. The usual treatment group had a total of 87 CBG measurements of <or=3.6 mmol/l during the study, and only 1 such measurement (3.5 mmol/l) was recorded in the GLP-1 group. Infusion of GLP-1 enhanced glucose-induced insulin secretion (pre: 119 +/- 21; post: 202 +/- 51 pmol/l; P < 0.05) and insulin-mediated glucose disposal (pre: 29.8 +/- 3.3; post: 35.9 +/- 2.3 micromol x kg(-1 x min(-1); P < 0.01). No effect of GLP-1 treatment was seen on the fasting plasma ghrelin levels. Although plasma ghrelin levels decreased during both portions of the clamp, a drug effect was not present. CONCLUSIONS: A GLP-1 compound is a promising therapeutic option for elderly diabetic patients.

Aged↗
PubMed2003

Effective exercise modality to reduce insulin resistance in women with type 2 diabetes.

OBJECTIVE: The purpose of this study was to evaluate whether a combined resistance and aerobic training program would improve insulin sensitivity compared with aerobic training alone in postmenopausal women with type 2 diabetes. A second objective was to relate the improved insulin sensitivity to changes in abdominal adipose tissue (AT) and thigh muscle density. RESEARCH DESIGN AND METHODS: A total of 28 obese postmenopausal women with type 2 diabetes were randomly assigned to one of three 16-week treatments: control, aerobic only training (Ae only), or aerobic plus resistance training (Ae+RT). Pre- and posttreatment outcome measures included glucose disposal by hyperinsulinemic-euglycemic clamp and computed tomography scans of abdominal AT and mid-thigh skeletal muscle. RESULTS: Glucose infusion rates increased significantly (P < 0.05) in the Ae+RT group. Both exercise groups had reduced abdominal subcutaneous and visceral AT and increased muscle density. The Ae+RT training group exhibited a significantly greater increase in muscle density than the Ae only group. Improved glucose disposal was independently associated with changes in subcutaneous AT, visceral AT, and muscle density. Muscle density retained a relationship with glucose disposal after controlling for abdominal AT. CONCLUSIONS: Adding resistance training to aerobic training enhanced glucose disposal in postmenopausal women with type 2 diabetes. The improved insulin sensitivity is related to loss of abdominal subcutaneous and visceral AT and to increased muscle density.

Adipose Tissue↗
PubMed2003

Effect of glucagon-like peptide 1 (7-36 amide) on insulin-mediated glucose uptake in patients with type 1 diabetes.

OBJECTIVE: To examine the insulinomimetic insulin-independent effects of glucagon-like peptide (GLP)-1 on glucose uptake in type 1 diabetic patients. RESEARCH DESIGN AND METHODS: We used the hyperinsulinemic-euglycemic clamp (480 pmol. m(-2) x min(-1)) in paired randomized studies of six women and five men with type 1 diabetes. In the course of one of the paired studies, the subjects also received GLP-1 at a dose of 1.5 pmol. kg(-1) x min(-1). The patients were 41 +/- 3 years old with a BMI of 25 +/- 1 kg/m(2). The mean duration of diabetes was 23 +/- 3 years. RESULTS: Plasma glucose was allowed to fall from a fasting level of approximately 11 mmol/l to 5.3 mmol/l in each study and thereafter was held stable at that level. Plasma insulin levels during both studies were approximately 900 pmol/l. Plasma C-peptide levels did not change during the studies. In the GLP-1 study, plasma total GLP-1 levels were elevated from the fasting level of 31 +/- 3 to 150 +/- 17 pmol/l. Plasma glucagon levels fell from the fasting levels of approximately 14 pmol/l to 9 pmol/l during both paired studies. Hepatic glucose production was suppressed during the glucose clamps in all studies. Glucose uptake was not different between the two studies ( approximately 40 micromol. kg(-1) x min(-1)). CONCLUSIONS: GLP-1 does not augment insulin-mediated glucose uptake in lean type 1 diabetic patients.

Adult↗
PubMed2002

Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes.

A gut insulinotropic peptide, glucagon-like peptide-1 (GLP-1), when given continuously subcutaneously, has been shown to be an effective agent to treat type 2 diabetes. Because of inactivation by dipeptidyl peptidase IV (DPP IV), it has a very short half-life (90-120 s), hence the need for continuous administration. Exendin-4 is an agonist of the GLP-1 receptor. It is not a substrate for DPP IV, and we previously demonstrated that intravenous administration has potent insulinotropic properties in type 2 diabetic volunteers. We evaluated the efficacy of bolus subcutaneous exendin-4 in insulin-naive type 2 diabetic volunteers. Ten patients aged 44-72 yr with mean fasting glucose levels of 11.4 +/- 0.9 mmol/l were enrolled, and daily or twice-daily bolus subcutaneous exendin-4 was self-administered for 1 mo. Glycosylated hemoglobin, multiple daily capillary blood glucose, beta-cell sensitivity to glucose, and peripheral tissue sensitivity to insulin were compared before and after treatment. The greatest decline in capillary blood glucose was seen before bed, with a drop from 15.5 to 9.2 mmol/l (P < 0.0001). Glycosylated hemoglobin improved significantly with treatment, from 9.1 to 8.3% (P = 0.009). beta-Cell sensitivity to glucose was improved, as assessed by C-peptide levels during a hyperglycemic clamp. No significant adverse effects were noted or reported. Our data suggest that, even with this short duration of therapy, exendin-4 treatment had a significant effect on glucose homeostasis.

Aged↗
PubMed2002

Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state.

The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is being examined as a potential new agent for treatment in type 2 diabetic patients. Whereas the insulinotropic properties of this peptide are well established, another property of the hormone, an insulinomimetic effect per se, is controversial. In the normal glucose-tolerant lean state, it is difficult to demonstrate an insulinomimetic effect. The current study was conducted to examine whether GLP-1 has insulinomimetic effect in the obese state. Ten obese volunteers (body mass index, 34.6 +/- 0.8 kg/m(2)), whose ages were 32.5 +/- 3.0 yr, participated in two euglycemic clamp studies (n = 20 clamps) for 120 min. Five of the volunteers were females. The initial clamp was performed with a primed (0-10)-constant (10-60) infusion of GLP-1 at a final rate of 1.5 pmol x kg(-1) x min(-1). At 60 min, the GLP-1 infusion was terminated, and euglycemic was maintained from 60-120 min. After the GLP-1 study, each individual's plasma insulin level was measured. A second study was performed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were regulated in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Fasting plasma insulin levels were similar between studies. In response to the GLP-1 infusion, with maintenance of plasma glucose level clamped at fasting level, significant increases in plasma insulin occurred in all subjects (P < 0.001). The insulin levels during the insulin infusion study were similar to that induced by GLP-1. The rate of disappearance of glucose (insulin-mediated glucose uptake) progressively increased in response to both the GLP-1 and insulin infusion. However, the rate of disappearance of glucose during the GLP-1 study was significantly higher (P = 0.033) than during the insulin study. We conclude that in insulin-resistant states, GLP-1 has insulinomimetic properties per se.

Adult↗
PubMed2002

Glucose tolerance, glucose utilization and insulin secretion in ageing.

Ageing is associated with an increased incidence of hypertension, macrovascular disease and type 2 diabetes (non-insulin-dependent diabetes). It has been suggested that a common mechanism may be responsible for all of these pathological states since all of these conditions often cluster in the same individual. Epidemiological and clinical data have consistently demonstrated an association between insulin resistance and/or hyperinsulinaemia and glucose intolerance, dyslipidaemia and elevated systolic blood pressures. Therefore, insulin resistance and hyperinsulinaemia have been proposed as the causal link among the elements of the clusters. The elderly are more glucose intolerant and insulin resistant, but it remains controversial whether this decrease in function is due to an inevitable consequence of 'biological ageing' or due to environmental or lifestyle variables, noticeably increased adiposity/altered fat distribution and physical inactivity. An increase of these modifiable factors has been shown to result in increases in insulin resistance and hyperinsulinaemia and vice versa. However, insulin secretion appears to decrease with age even after adjustments for differences in adiposity, fat distribution and physical activity. The glucose intolerance of ageing may be due, in part, to decreased insulin sensitivity of pancreatic / cells to insulinotropic gut hormones (GLP1/GIP) and in part to alterations of hepatic glucose production.

Aging↗