Aims: To investigate the contributions of two factors potentially impairing glucagon response to insulin-induced hypoglycemia (IIH) in insulin-deficient diabetes: 1. loss of paracrine disinhibition by intra-islet insulin, 2. defects in the activation of the autonomic inputs to the islet. Methods: Plasma glucagon responses during hyperinsulinemic-hypoglycemic clamps ( 40 mg/dL) were assessed in dogs with spontaneous diabetes (n=13) and healthy non-diabetic dogs (n=6). Plasma C-peptide responses to intravenous glucagon were measured to assess endogenous insulin secretion. Plasma pancreatic polypeptide (PP), epinephrine (EPI) and norepinephrine (NE) were measured as indices of parasympathetic and sympathoadrenal autonomic responses to IIH. Results: In 8 of 13 diabetic dogs, glucagon did not increase during IIH (DMN; ∆ = -6±12 pg/mL). In 5 other diabetic dogs (DMR) glucagon responses (∆ = +26±12) were within the range of non-diabetic control dogs (∆ = +27±16 pg/mL). C-peptide responses to IV glucagon were absent in diabetic dogs. Activation of all three autonomic responses were impaired in DMN dogs but remained intact in DMR dogs. Each of the three autonomic responses to IIH was positively correlated with glucagon responses across the 3 groups. Conclusions: 1) Impairment of glucagon responses in DMN dogs is not due to generalized impairment of alpha-cell function. 2) Loss of tonic inhibition of glucagon secretion by insulin is not sufficient to produce loss of the glucagon response; impairment of autonomic activation is also required. 3) In dogs with major beta-cell function loss, activation of the autonomic inputs is sufficient to mediate an intact glucagon response to IIH.

中文翻译：

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自然发生的胰岛素依赖型糖尿病犬对胰岛素诱导的低血糖的自主神经和胰高血糖素反应的共同损害

目的：研究可能损害胰高血糖素对胰岛素缺乏型糖尿病中胰岛素诱导低血糖 (IIH) 反应的两个因素的贡献：1. 胰岛内胰岛素对旁分泌抑制的丧失，2. 自主神经输入激活缺陷小岛。方法：在患有自发性糖尿病的犬 (n=13) 和健康的非糖尿病犬 (n=6) 中评估高胰岛素-低血糖钳夹 (40 mg/dL) 期间的血浆胰高血糖素反应。测量血浆 C 肽对静脉内胰高血糖素的反应以评估内源性胰岛素分泌。血浆胰多肽 (PP)、肾上腺素 (EPI) 和去甲肾上腺素 (NE) 被测量为副交感神经和交感肾上腺对 IIH 的自主反应的指数。结果：13 只糖尿病犬中有 8 只在 IIH 期间胰高血糖素没有增加（DMN；Δ = -6±12 pg/mL）。在其他 5 只糖尿病犬 (DMR) 中，胰高血糖素反应 (Δ = +26±12) 在非糖尿病对照犬的范围内 (Δ = +27±16 pg/mL)。糖尿病犬不存在对静脉注射胰高血糖素的 C 肽反应。所有三种自主反应的激活在 DMN 犬中均受损，但在 DMR 犬中保持完整。对 IIH 的三种自主神经反应中的每一种都与 3 组的胰高血糖素反应呈正相关。结论：1) DMN 犬胰高血糖素反应的损害不是由于 α 细胞功能的普遍损害。2) 胰岛素对胰高血糖素分泌的强直性抑制的丧失不足以导致胰高血糖素反应的丧失；自主神经激活受损也是必需的。3) 在主要 β 细胞功能丧失的狗中，自主神经输入的激活足以介导对 IIH 的完整胰高血糖素反应。