We tested the hypotheses that the glucagon response to hypoglycemia is reduced in patients who are approaching the insulin-deficient end of the spectrum of type 2 diabetes and that recent antecedent hypoglycemia shifts the glycemic thresholds for autonomic (including adrenomedullary epinephrine) and symptomatic responses to hypoglycemia to lower plasma glucose concentrations in type 2 diabetes. Hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) were performed on two consecutive days, with an additional 2 h of hypoglycemia (50 mg/dl) in the afternoon of the first day, in 13 patients with type 2 diabetes-7 treated with oral hypoglycemic agents (OHA R X ; mean [؎SD] HbA 1c 8.6 ؎ 1.1%) and 6 requiring therapy with insulin for an average of 5 years and with reduced C-peptide levels (insulin R X , HbA 1c 7.5 ؎ 0.7%)-and 15 nondiabetic control subjects. The glucagon response to hypoglycemia was virtually absent (P ‫؍‬ 0.0252) in the insulin-deficient type 2 diabetic patients (insulin R X mean [؎SE] final values of 52 ؎ 16 vs. 93 ؎ 15 pg/ml in control subjects and 98 ؎ 16 pg/ml in type 2 diabetic patients, OHA R X on day 1). Glucagon (P ‫؍‬ 0.0015), epinephrine (P ‫؍‬ 0.0002), and norepinephrine (P ‫؍‬ 0.0138) responses and neurogenic (P ‫؍‬ 0.0149) and neuroglycopenic (P ‫؍‬ 0.0015) symptom responses to hypoglycemia were reduced on day 2 after hypoglycemia on day 1 in type 2 diabetic patients; these responses were not eliminated, but their glycemic thresholds were shifted to lower plasma glucose concentrations. In addition, the glycemic thresholds for these responses were at higher-than-normal plasma glucose concentrations (P ‫؍‬ 0.0082, 0.0028, 0.0023, and 0.0182, respectively) at baseline (day 1) in OHA R X type 2 diabetic patients, with relatively poorly controlled diabetes. Because the glucagon response to falling plasma glucose levels is virtually absent and the glycemic thresholds for autonomic and symptomatic responses to hypoglycemia are shifted to lower glucose concentrations by recent antecedent hypoglycemia, patients with advanced type 2 diabetes, like those with type 1 diabetes, are at risk for hypoglycemia-associated autonomic failure and the resultant vicious cycle of recurrent iatrogenic hypoglycemia. Diabetes 51:724 -733, 2002

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Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after ϳ24 h of interprandial hypoglycemia (ϳ55 mg/dl, ϳ3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P ‫؍‬ 0.009), neurogenic symptoms (P ‫؍‬ 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain timeactivity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1- , respectively), cerebral glucose metabolism (16.8 ؎ 0.9 and 15.9 ؎ 0.9 mol ⅐ 100 g ؊1 ⅐ min ؊1 , respectively) and cerebral blood flow (56.8 ؎ 3.9 and 53.3 ؎ 4.4 ml ⅐ 100 g ؊1 ⅐ min ؊1 , respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.

Background Immunoglobulin-G4-related hypophysitis is a rare inflammatory disease that can present as a tumefactive pituitary lesion mimicking hypophyseal neoplasms such as pituitary adenoma or craniopharyngioma. The literature on this entity is sparse, with fewer than 100 cases reported across 19 publications; a recent review found only 24 cases published from 2007 to 2018. Previous reports have described demographic differences, with immunoglobulin-G4-related hypophysitis in females tending to present in the second and third decades in association with other autoimmune disease, while males tend to present in the fifth and sixth decades of life without an autoimmune history. Case presentation In contrast to the reported demographic trends, here we describe a unique case of immunoglobulin-G4-related hypophysitis in a 63-year-old white female with no history of autoimmune disease who presented with a rapidly enlarging sellar and hypothalamic mass causing headaches and cranial nerve palsies, prompting biopsy for diagnosis. The patient experienced rapid response to treatment with high-dose steroids and rituximab. Conclusion The case contributes to the growing clinicopathologic description of immunoglobulin-G4-related hypophysitis and illustrates that this diagnosis should be a consideration even outside the conventional demographic setting.