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OBJECTIVE-Amino acids stimulate glucagon responses to hypoglycemia and may be utilized by the brain. The aim of this study was to assess the responses to hypoglycemia in nondiabetic and type 1 diabetic subjects after ingestion of an amino acid mixture.RESEARCH DESIGN AND METHODS-Ten nondiabetic and 10 diabetic type 1 subjects were studied on three different occasions during intravenous insulin (2 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ) plus variable glucose for 160 min. In two studies, clamped hypoglycemia (47 mg/dl plasma glucose for 40 min) was induced and either oral placebo or an amino acid mixture (42 g) was given at 30 min. In the third study, amino acids were given, but euglycemia was maintained.RESULTS-Plasma glucose and insulin were no different in the hypoglycemia studies with both placebo and amino acids (P Ͼ 0.2). After the amino acid mixture, plasma amino acid concentrations increased to levels observed after a mixed meal (2.4 Ϯ 0.13 vs. placebo study 1.7 Ϯ 0.1 mmol/l, P ϭ 0.02). During clamped euglycemia, ingestion of amino acids resulted in transient increases in glucagon concentrations, which returned to basal by the end of the study. During clamped hypoglycemia, glucagon response was sustained and increased more in amino acid studies versus placebo in nondiabetic and diabetic subjects (P Ͻ 0.05), but other counter-regulatory hormones and total symptom score were not different. ␤-OH-butyrate was less suppressed after amino acids (200 Ϯ 15 vs. 93 Ϯ 9 mol/l, P ϭ 0.01). Among the cognitive tests administered, the following indicated less deterioration after amino acids than placebo: Trail-Making part B, PASAT (Paced Auditory Serial Addition Test) (2 s), digit span forward, Stroop colored words, and verbal memory tests for nondiabetic subjects; and Trail-Making part B, digit span backward, and Stroop color tests for diabetic subjects.CONCLUSIONS-Oral amino acids improve cognitive function in response to hypoglycemia and enhance the response of glucagon in nondiabetic and diabetic subjects.

OBJECTIVE-The acylated long-acting insulin analog detemir is more lipophilic than human insulin and likely crosses the blood-to-brain barrier more easily than does human insulin. The aim of these studies was to assess the brain/hypothalamus responses to euglycemia and hypoglycemia in humans during intravenous infusion of equipotent doses of detemir and human insulin.RESEARCH DESIGN AND METHODS-Ten normal, nondiabetic subjects (six men, age 36Ϯ7 years, and BMI 22.9Ϯ2.6 kg/m 2 ) were studied on four occasions at random during intravenous infusion of either detemir or human insulin in euglycemia (plasma glucose 90 mg/dl) or during stepped hypoglycemia (plasma glucose 90, 78, 66, 54, and 42 mg/dl steps).RESULTS-Plasma counterregulatory hormone response to hypoglycemia did not differ between detemir and human insulin. The glycemic thresholds for adrenergic symptoms were higher with detemir (51 Ϯ 7.7 mg/dl) versus human insulin (56 Ϯ 7.8 mg/dl) (P ϭ 0.029). However, maximal responses were greater with detemir versus human insulin for adrenergic (3 Ϯ 2.5 vs. 2.4 Ϯ 1.8) and neuroglycopenic (4 Ϯ 3.9 vs. 2.7Ϯ2.5) symptoms (score, P Ͻ 0.05). Glycemic thresholds for onset of cognitive dysfunction were lower with detemir versus human insulin (51 Ϯ 8.1 vs. 47 Ϯ 3.6 mg/dl, P ϭ 0.031), and cognitive function was more deteriorated with detemir versus human insulin (P Ͻ 0.05). CONCLUSIONS-Compared with human insulin, responses tohypoglycemia with detemir resulted in higher glycemic thresholds for adrenergic symptoms and greater maximal responses for adrenergic and neuroglycopenic symptoms, with an earlier and greater impairment of cognitive function. Additional studies are needed to establish the effects of detemir on responses to hypoglycemia in subjects with diabetes. Diabetes 57:746-756, 2008 T he physiology of glucose counterregulation to hypoglycemia in humans has been extensively studied (1). A progressive decline in plasma glucose induced by insulin triggers a well-established sequence of hierarchic responses that occur at specific glycemic thresholds (2-4).It is important that new insulin formulations and/or insulin analogs available for treatment of diabetes are compared with the reference human insulin for thresholds of responses and overall responses to hypoglycemia to exclude additional risks of inducing hypoglycemia unawareness. The rapid-acting insulin analogs lispro (5) and aspart (6) and the long-acting analog glargine (7) have been shown to be no different in terms of responses to hypoglycemia versus human insulin. Regarding the longacting insulin analog detemir, there are no systematic observations with the exception of two preliminary studies-one in normal, nondiabetic subjects (8) and the other in subjects with type 1 diabetes (9)-with conflicting results.Insulin detemir is a long-acting soluble insulin analog with a 14 C fatty acid chain conferring lipophility, associated with free fatty acid (FFA) binding sites on albumin (10). Because of these characteristics, the responses of insulin detemir to hypoglycemi...

Aims/hypothesis The aim of our study was to establish whether the well-known defective or absent secretion of glucagon in type 1 diabetes in response to hypoglycaemia is selective or includes lack of responses to other stimuli, such as amino acids. Materials and methods Responses of glucagon to hypoglycaemia were measured in eight patients with type 1 diabetes and six non-diabetic subjects during hyperinsulinaemic (insulin infusion 0.5 mU kg −1 min −1 ) and eu-, hypo-and hyperglycaemic clamp studies (sequential steps of plasma glucose 5.0, 2.9, 5.0, 10 mmol/l). Subjects were studied on three randomised occasions with infusion of low-or high-dose alanine, or saline. Results With saline, glucagon increased in hypoglycaemia in non-diabetic subjects but not in diabetic subjects. Glucagon increased further with low-dose (181±16 ng l −1 min −1 ) and high-dose alanine (238±20 ng l −1 min −1 ) in non-diabetic subjects, but only with high-dose alanine in diabetic subjects (area under curve 112±5 ng l −1 min −1 ). The alanine-induced glucagon increase in diabetic subjects paralleled the spontaneous glucagon response to hypoglycaemia in non-diabetic subjects not receiving alanine. The greater responses of glucagon to hypoglycaemia with alanine infusion were offset by recovery of eu-or hyperglycaemia.

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