Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis.

Fanelli, Carmine G.; Feo, Pierpaolo De; Porcellati, Francesca; Perriello, G.; Torlone, E.; Santeusanio, Fausto; Brunetti, P; Bolli, GB

doi:10.1172/jci115809

Cited by 85 publications

(66 citation statements)

References 71 publications

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“…A1C was determined by highperformance liquid chromatography using an HI-Auto A 1 c TM HA 8121 apparatus (DIC; Kyoto Daaichi Kogaku, Kyoto, Japan) (Diabetes Control and Complications Trial aligned nondiabetic subjects Ͻ6.1%). Plasma glycerol, ␤-hydroxybutyrate, lactate, and alanine were measured by previously described fluorometric assays (16). Plasma free fatty acid (FFA) concentrations were measured using a commercial kit (NEFA C test kit; Wako Chemicals, Neuss, Germany).…”

Section: Methodsmentioning

confidence: 99%

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes

et al. 2007

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OBJECTIVE -To compare pharmacokinetics and pharmacodynamics of insulin analogs glargine and detemir, 24 subjects with type 1 diabetes (aged 38 Ϯ 10 years, BMI 22.4 Ϯ 1.6 kg/m 2 , and A1C 7.2 Ϯ 0.7%) were studied after a 2-week treatment with either glargine or detemir once daily (randomized, double-blind, crossover study).RESEARCH DESIGN AND METHODS -Plasma glucose was clamped at 100 mg/dl for 24 h after subcutaneous injection of 0.35 unit/kg. The primary end point was end of action (time at which plasma glucose was Ͼ150 mg/dl).RESULTS -With glargine, plasma glucose remained at 103 Ϯ 3.6 mg/dl up to 24 h, and all subjects completed the study. Plasma glucose increased progressively after 16 h with detemir, and only eight subjects (33%) completed the study with plasma glucose Ͻ180 mg/dl. Glucose infusion rate (GIR) was similar with detemir and glargine for 12 h, after which it decreased more rapidly with detemir (P Ͻ 0.001). Estimated total insulin activity (GIR area under the curve [AUC] 0 -end of GIR ) was 1,412 Ϯ 662 and 915 Ϯ 225 mg/kg (glargine vs. detemir, P Ͻ 0.05), with median time of end of action at 24 and 17.5 h (glargine vs. detemir, P Ͻ 0.001). The antilipolytic action of detemir was lower than that of glargine (AUC free fatty acids 0 -24 h 11 Ϯ 1.7 vs. 8 Ϯ 2.8 mmol/l, respectively, P Ͻ 0.001).CONCLUSIONS -Detemir has effects similar to those of glargine during the initial 12 h after administration, but effects are lower during 12-24 h.

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Section: Methodsmentioning

confidence: 99%

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes

et al. 2007

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“…Plasma insulin, glucagon, adrenaline, noradrenaline, glycerol, β-hydroxybutyrate, lactate and alanine were measured by previously described assays [15][16][17]. To remove antibodybound insulin, plasma was mixed with an equal volume of 30% polyethylene glycol immediately after blood collection in both diabetic and non-diabetic subjects [17].…”

Section: Methodsmentioning

confidence: 99%

Effect of the amino acid alanine on glucagon secretion in non-diabetic and type 1 diabetic subjects during hyperinsulinaemic euglycaemia, hypoglycaemia and post-hypoglycaemic hyperglycaemia

et al. 2006

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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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“…Plasma glucose was measured using a Beckman Glucose Analyzer (Beckman Instruments, Palo Alto, Calif., USA). Plasma insulin, growth hormone, cortisol, adrenaline and noradrenaline [31] and pancreatic polypeptide [32] were measured by previously described assays. To remove antibody-bound insulin, plasma was mixed with an equal volume of 30 % polyethylene glycol immediately after blood collection [29].…”

Section: Subjectsmentioning

confidence: 99%

Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM

et al. 1994

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Summary Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on "conventional" insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and i year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n = 16), or maintenance of the original "conventional" therapy (control group, CON, n = 5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXR the frequency of hypoglycaemia decreased from 0.5 + 0.05 to 0.045 _+ 0.02 episodes/patient-day; HbAlc increased from 5.83 + 0.18 to 6.94 + 0.13 % (range in non-diabetic subjects 3.8-5.5 %) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p < 0.05). The improvement in responses was maintained at i year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

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Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis.

Cited by 85 publications

References 71 publications

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes

Comparison of Pharmacokinetics and Dynamics of the Long-Acting Insulin Analogs Glargine and Detemir at Steady State in Type 1 Diabetes

Effect of the amino acid alanine on glucagon secretion in non-diabetic and type 1 diabetic subjects during hyperinsulinaemic euglycaemia, hypoglycaemia and post-hypoglycaemic hyperglycaemia

Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM

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