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Heise, T.; Heinemann, L.; Heller, S.; Weyer, C.; Wang, Y.; Strobel, S.; Kolterman, O.; Maggs, D. |
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Title |
Effect of pramlintide on symptom, catecholamine, and glucagon responses to hypoglycemia in healthy subjects |
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Journal Article |
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Year |
2004 |
Publication |
Metabolism |
Abbreviated Journal |
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53 |
Issue |
9 |
Pages |
1227-1232 |
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Keywords |
Adolescent; Adult; Amyloid; Autonomic Nervous System; Blood Glucose; Body Mass Index; Catecholamines; Cross-Over Studies; Double-Blind Method; Female; Glucagon; Glucose Clamp Technique; Humans; Hypoglycemia; Hypoglycemic Agents; Kinetics; Male |
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Pramlintide is an analog of the human glucoregulatory hormone amylin. Previous studies have shown no clear evidence that pramlintide modifies the response to insulin-induced hypoglycemia; however, a detailed assessment of responses at hypoglycemic thresholds has not been conducted. To further test the effect of pramlintide on symptom, catecholamine, and glucagon responses, a 3-step hypoglycemic clamp was investigated in healthy volunteers. In a randomized, double-blind, placebo-controlled, crossover study, 18 healthy subjects without diabetes received subcutaneous premeal injections of either placebo or 60 microg pramlintide 3 times daily for 5 consecutive days. On day 6, subjects received study drug with breakfast and, after a 7-hour fast, were connected to a Biostator for a 3-step, 3-hour clamp experiment (insulin infusion rate: 1.0 mU/kg/min; blood glucose targets: 70, 55, and 45 mg/dL). An intravenous (IV) infusion of pramlintide (16 microg/h) or placebo was initiated at t = 60 minutes. At the end of each 60-minute clamp step, autonomic (sweating, palpitations, hunger, etc) and neuroglycopenic (confusion, headache, odd behavior, etc) symptoms were assessed using a validated visual analog scale questionnaire. Blood samples were collected at 30-minute intervals for measurement of plasma glucose, insulin, pramlintide, catecholamine, and glucagon concentrations. Intraindividual and group mean responses showed that autonomic symptoms and plasma catecholamine and glucagon concentrations increased progressively during the clamp, with no discernible differences between pramlintide and placebo treatments. Group means for catecholamines at 60 minutes were: epinephrine 233 +/- 42, 892 +/- 85, 2,340 +/- 302 and 202 +/- 25, 774 +/- 114, 2,751 +/- 404 pg/mL and norepinephrine 1,138 +/- 86, 1,236 +/- 77, 1,721 +/- 158 and 1,278 +/- 108, 1,259 +/- 109, 1,580 +/-136 pg/mL (+/- SEM) for placebo- and pramlintide-treated groups at 70, 55, and 45 mg/dL glucose, respectively. Group means for glucagon were 72 +/- 6.3, 98 +/- 11.1, 130 +/- 14.7 and 63 +/- 3.6, 92 +/- 9.4, 120 +/- 16.0 pmol/L (+/- SEM) for placebo- and pramlintide-treated groups at 70, 55, and 45 mg/dL glucose, respectively. These results showed that pramlintide did not impair the symptom, catecholamine, and glucagon responses to insulin-induced hypoglycemia in healthy subjects. |
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0026-0495 |
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refbase @ user @ Heise2004 |
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2215 |
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Author |
Heller, S. |
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Title |
Weight gain during insulin therapy in patients with type 2 diabetes mellitus |
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Journal Article |
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Year |
2004 |
Publication |
Diabetes Res Clin Pract |
Abbreviated Journal |
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65 Suppl 1 |
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S23-S27 |
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Keywords |
Blood Glucose; Diabetes Mellitus, Type 2; Exercise; Humans; Hypoglycemic Agents; Insulin; Obesity; Patient Education as Topic; Weight Gain |
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Abstract |
In patients with diabetes, the benefits of tight glycemic control are unequivocal--delayed onset and progression of complications such as retinopathy, nephropathy, and neuropathy. However, intensive therapy with insulin and some oral antidiabetic agents come at the price of weight gain, a condition that can prevent attainment of tight glycemic goals and probably limits success of treatment. Insulin-related weight gain has been attributed to anabolic effects of insulin, appetite increases, and reduction of glycosuria. Use of metformin in combination with insulin is commonly recommended as a way to limit weight gain in patients with type 2 diabetes, and other new oral therapies and insulin analogs may also provide weight-control advantages. Lifestyle interventions (patient education about diet and exercise) promote weight loss in the short-term, but have not sustained weight control over long-term intervals. For lasting weight control, such interventions may need to continue throughout the course of treatment. Likewise, weight-loss agents, such as sibutramine and orlistat promote short-term weight loss, but no follow-up studies have yet demonstrated that this loss can be maintained for 5 years or longer. Bariatric surgery is the only treatment recognized to have lasting effects on weight control, but its use is limited at present to those who are morbidly obese. |
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0168-8227 |
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2216 |
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Lee, S.P.; Yeoh, L.; Harris, N.D.; Davies, C.M.; Robinson, R.T.; Leathard, A.; Newman, C.; Macdonald, I.A.; Heller, S.R. |
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Title |
Influence of autonomic neuropathy on QTc interval lengthening during hypoglycemia in type 1 diabetes |
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Journal Article |
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Year |
2004 |
Publication |
Diabetes |
Abbreviated Journal |
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53 |
Issue |
6 |
Pages |
1535-1542 |
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Keywords |
Adult; Autonomic Nervous System; Autonomic Nervous System Diseases; Blood Pressure; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Electrocardiography; Epinephrine; Female; Glucose Clamp Technique; Heart; Humans; Hypoglycemia; Male; Norepinephrine; Potassium |
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Hypoglycemia produces electrocardiographic QTc lengthening, a predictor of arrhythmia risk and sudden death. This results from both sympatho-adrenal activation and a lowered serum potassium. It has been suggested that cardiac autonomic neuropathy (CAN) might indicate those who are at particular risk. We tested this hypothesis in 28 adults with type 1 diabetes and 8 nondiabetic control subjects. After standard tests of autonomic function and baroreflex sensitivity (BRS) measurement, diabetic participants were divided into three groups: 1) CAN- with normal BRS (BRS+; n = 10), 2) CAN- with impaired BRS (BRS-; n = 9), and 3) CAN+ (n = 9). QTc was then measured during controlled hypoglycemia (2.5 mmol/l) using a hyperinsulinemic clamp. Mean (+/-SE) QTc lengthened from 377 +/- 9 ms (baseline) to a maximum during hypoglycemia of 439 +/- 13 ms in BRS+ subjects and from 378 +/- 5 to 439 +/- 10 ms in control subjects. Peak QTc tended to be lower in CAN+ (baseline, 383 +/- 6; maximum, 408 +/- 10) and BRS- groups (baseline, 380 +/- 8; maximum, 421 +/- 11; F = 1.7, P = 0.18). Peak epinephrine concentrations (nmol/l) were 3.1 +/- 0.8 (BRS+), 2.6 +/- 0.5 (BRS-), 1.4 +/- 0.3 (CAN+), and 5.7 +/- 0.8 (control subjects). These data do not indicate that those with CAN are at particular risk for abnormal cardiac repolarization during hypoglycemia. Indeed, they suggest that such patients may be relatively protected, perhaps as a result of attenuated sympatho-adrenal responses. |
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0012-1797 |
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refbase @ user @ Lee2004 |
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2217 |
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Author |
Heller, S. |
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Title |
Insulin lispro: a useful advance in insulin therapy |
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Journal Article |
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Year |
2003 |
Publication |
Expert Opin Pharmacother |
Abbreviated Journal |
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4 |
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8 |
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1407-1416 |
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Clinical Trials as Topic; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Pregnancy |
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Insulin lispro, the first insulin analogue to be used clinically, was engineered to incorporate the pharmacological advantages of insulin-like growth factor-1 (IGF-1), which has a reduced tendency to self associate, compared to conventional soluble insulin. It is absorbed more quickly following a subcutaneous injection, reaching peak concentrations (approximately twice as much as conventional insulin) and then falls more rapidly. These more physiological insulin profiles are reflected in the results of clinical trials involving patients with Type 1 diabetes, which generally show comparable glycaemic control but reduced rates of hypoglycaemia, particularly at night. The reduction in the rate of hypoglycaemia in the early trials has been generally fairly modest, but more recent publications suggest that increasing experience and more individualised insulin adjustment may lead to a greater impact. Other indications include its use in continuous subcutaneous insulin infusion and postprandially in young children. |
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1465-6566 |
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refbase @ user @ Heller2003 |
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2218 |
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Author |
Heller, S. |
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Title |
The National Service Framework for Diabetes: a glass half empty or half full? |
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Journal Article |
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2003 |
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Diabet Med |
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20 |
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3 |
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173-174 |
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Delivery of Health Care; Diabetes Mellitus; Great Britain; Health Planning; Humans |
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0742-3071 |
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refbase @ user @ Heller2003 |
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2220 |
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