Insulin-associated modulation of neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus: evidence for an intrinsic effect of insulin on the central nervous system.

Lingenfelser, Thomas; Overkamp, D.; Renn, W.; Buettner, U. W.; Kimmerle, K; Schmalfuss, A; Jakober, B.

doi:10.1210/jcem.81.3.8772600

Cited by 22 publications

(26 citation statements)

References 45 publications

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“…Circulating insulin appears to have no direct effect on glucose utilisation in the brain, despite recent observations in hypoglycaemic dogs and humans that the brain is sensitive to insulin [22,23]. In agreement with previous findings in dogs [24], brain glucose utilisation was of similar magnitude irrespective of the fall in circulating glucose from 4.8 to 2.4 mmol/l ( Table 1).…”

Section: Discussionsupporting

confidence: 88%

Brain substrate utilisation during acute hypoglycaemia

et al. 1999

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It is now clearly established that tight blood glucose control substantially reduces or delays most of the chronic complications in patients with Type I (insulin-dependent) diabetes mellitus [1]. A tight blood glucose control, however, is accompanied by increased hypoglycaemic episodes [1]. These recurrent hypoglycaemic episodes are major impediments in achieving ideal blood glucose control in a substantial number of Type I diabetic patients. In studies where alternative fuels, such as b-hydroxybutyrate and lactate [2] were provided in attempts to alleviate hypoglycaemic symptoms, the response of the autonomic system to hypoglycaemia was diminished or prevented [3]. Based on this indirect evidence, it was concluded that the brain uses these alternative fuels during hypoglycaemia. The brain contains the enzyme systems that are required for the metabolism of a range of different carbohydrate and lipid substrates [4]. There is thus, no immediate reason why the brain Diabetologia (1999) AbstractAims/hypothesis. Our study was undertaken to examine directly the utilisation of glucose and alternative substrates, in particular amino acids, during hypoglycaemia.Methods. Catheters were positioned in the jugular venous bulb and an artery in six healthy subjects in the overnight fasted state. Arterio-venous differences for glucose, amino acids, lactate and pyruvate were measured in the basal state, during hyperinsulinaemic euglycaemia and during hyperinsulinaemic hypoglycaemia. The subjects were studied on two different occasions, once during intravenous infusion of amino acids and once during infusion of saline.Results. In the basal state the fractional extraction of glucose across the brain was 10 ± 2 %, glucose uptake accounted for 106 ± 5 % of the brain's oxidative metabolism. There was a small release of lactate and pyruvate. During hyperinsulinaemia glucose uptake continued to account for the entire fuel requirement

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Section: Discussionsupporting

confidence: 88%

Brain substrate utilisation during acute hypoglycaemia

et al. 1999

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“…With regard to responses to hypoglycemia, the evidence, although not uniformly in agreement, indicates that higher plasma insulin concentrations, which imply higher cerebral insulin concentrations, may elicit greater counterregulatory responses, increased symptoms, and deterioration of cognitive function to insulin-induced hypoglycemia (20). The best evidence for such conclusions is provided by Lingenfelser et al (19), who performed hyperinsulinemic stepped hypoglycemic clamps in subjects with type 1 diabetes. The results of our study, which might be related to a higher concentration of insulin detemir in the brain, fit well within this framework.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, plasma concentrations of insulin detemir are greater than those of human insulin because of its binding to albumin (15) and because of its higher (four time) molar concentration than human insulin (16). This might directly influence counterregulatory responses because high plasma concentrations of insulin might modulate per se counterregulation to hypoglycemia (17)(18)(19)(20)(21)(22).The aim of the present study was to compare the physiological responses (counterregulatory hormones, symptoms, and impairment of cognitive function) to hypoglycemia induced by equipotent doses of insulin detemir and regular human insulin. Healthy subjects were studied during stan- …”

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confidence: 99%

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Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

et al. 2008

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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...

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“…Under conditions of hypoglycemia, when the autonomic nervous system is activated, elevated insulin levels have been shown to inhibit (9), augment (10 -14), or not significantly effect (15)(16)(17)(18)) the sympathoadrenal response. Insulin may also alter the hypothalamicpituitary-adrenal response as noted by an insulin-mediated augmentation of the cortisol response to hypoglycemia that was significant in some (10,11,14) but not all (12,13,17,18) studies. Although the site of insulin action was not identified in these studies, it has been suggested that circulating insulin crosses the blood-brain barrier to directly activate the autonomic nervous system.…”

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Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

et al. 2005

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Hypoglycemia, hypoglycemia unawareness, and impaired counterregulation are major challenges to the intensive management of type 1 diabetes. While the counterregulatory response to hypoglycemia is predominantly determined by the degree and duration of hypoglycemia, there is now evidence that insulin per se may influence the counterregulatory response to hypoglycemia. To define the role of insulin action in the central nervous system in regulating the counterregulatory response to hypoglycemia, mice with a brain/neuron-specific insulin receptor knockout (NIRKO) and littermate controls were subjected to 90-min hyperinsulinemic (20 mU ⅐ kg ؊1 ⅐ min ؊1 ) -hypoglycemic (ϳ1.5 mmol/l) clamps. In response to hypoglycemia, epinephrine levels rose 5.7-fold in controls but only 3.5-fold in NIRKO mice. Similarly, in response to hypoglycemia, norepinephrine levels rose threefold in controls, but this response was almost completely absent in NIRKO mice. In contrast, glucagon and corticosterone responses to hypoglycemia were similar in both groups. Thus, insulin action in the brain is critical for full activation of the sympathoadrenal response to hypoglycemia, and altered neural insulin signaling could contribute to defective glucose counterregulation in diabetes.

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Insulin-associated modulation of neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus: evidence for an intrinsic effect of insulin on the central nervous system.

Cited by 22 publications

References 45 publications

Brain substrate utilisation during acute hypoglycaemia

Brain substrate utilisation during acute hypoglycaemia

Different Brain Responses to Hypoglycemia Induced by Equipotent Doses of the Long-Acting Insulin Analog Detemir and Human Regular Insulin in Humans

Insulin Signaling in the Central Nervous System Is Critical for the Normal Sympathoadrenal Response to Hypoglycemia

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