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Dive into the research topics where Philip E. Cryer is active.

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Featured researches published by Philip E. Cryer.


Diabetes Care | 2003

Hypoglycemia in Diabetes

Philip E. Cryer; Stephen N. Davis; Harry Shamoon

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemias long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA(1c) levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.


Neurobiology of Aging | 1996

Memory improvement following induced hyperinsulinemia in alzheimer's disease

Suzanne Craft; John W. Newcomer; Stephen M. Kanne; Samuel Dagogo-Jack; Philip E. Cryer; Yvette I. Sheline; Joan L. Luby; Agbani Dagogo-Jack; Amy L. Alderson

Dementia of the Alzheimer type (DAT) is accompanied by disruption in glucose regulation and utilization that may contribute to its characteristic memory impairment. Increasing glucose availability by raising plasma glucose improves memory in patients with DAT. Such memory improvement is associated with a secondary elevation in plasma insulin levels, raising the question of whether improvement is due to changes in insulin levels, independent of hyperglycemia. Distributions of insulin receptors in the hippocampus and insulin-mediated increases in glucose utilization in entorhinal cortex provide potential mechanisms for such improvement. We show that raising plasma insulin through intravenous infusion while keeping plasma glucose at a fasting baseline level produces striking memory enhancement for patients with DAT. Previous findings of hyperglycemic memory enhancement were also replicated. Patients with DAT also showed abnormal plasma levels of glucoregulatory hormones and metabolites at baseline and during metabolic manipulations. Our findings suggest that neuroendocrine factors play an important role in the pathophysiology of DAT.


Ophthalmology | 1981

The natural history of retinopathy in insulin-dependent juvenile-onset diabetes

Paul F. Palmberg; Morton E. Smith; Stephen R. Waltman; Theodore Krupin; Paul Singer; Dean B. Burgess; Thomas Wendtlant; Joel Achtenberg; Philip E. Cryer; Julio V. Santiago; Neil H. White; Charles Kilo; William H. Daughaday

We determined the cross-sectional natural history of retinopathy by prospective study of 461 insulin-dependent juvenile-onset diabetics. In so doing, we compared the sensitivity of ophthalmoscopy, photography, and fluorescein angiography in detecting retinopathy. Photography was far more reliable than ophthalmoscopy in detecting early retinopathy and equivalent to angiography. Retinopathy was not present at diagnosis of diabetes. After a lag period, the prevalence of retinopathy rose in sigmoidal fashion, reaching 50% at just over seven years duration, and asymptotically approaching 90% at 17--50 years. Proliferative retinopathy was first seen at 13 years duration, and its prevalence rose to 26% at 26--50 years. From the natural history we computed the dimensions of a proposed clinical trial to test the effect of tight metabolic control in prevention of retinopathy.


Diabetes Care | 1993

Hypoglycemia Unawareness in IDDM

Philip E. Cryer

Hypoglycemia unawareness—loss of the neurogenic (autonomic) warning symptoms of developing hypoglycemia—is one of three hypoglycemia-associated clinical syndromes that exemplify hypoglycemia-associated autonomic failure in IDDM. Reduced awareness of developing hypoglycemia (an elevated glycemic threshold for symptoms) is a feature not only of hypoglycemia unawareness but also of the syndromes of defective glucose counterregulation, elevated glycemic thresholds for symptoms, and activation of glucose counterregulatory systems during effective intensive therapy. These syndromes are major risk factors for severe iatrogenic hypoglycemia in individuals with IDDM. Their pathogenesis is unknown and likely multifactorial. Recent antecedent iatrogenic hypoglycemia may be one factor, perhaps a major factor, that, by reducing both the symptoms of and defenses against developing hypoglycemia, results in recurrent iatrogenic hypoglycemia, thus creating a vicious cycle. On the other hand, treatment with human compared with animal insulin does not appear to be an important factor.


Endocrinology and Metabolism Clinics of North America | 1999

Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness

Philip E. Cryer

Ultimately traceable to neural glucose deprivation, symptoms of hypoglycemia include neurogenic (autonomic) and neuroglycopenic symptoms. Neurogenic symptoms (tremulousness, palpitations, anxiety, sweating, hunger, paresthesias) are the results of the perception of physiologic changes caused by the autonomic nervous systems response to hypoglycemia. Neuroglycopenic symptoms (confusion, sensation of warmth, weakness or fatigue, severe cognitive failure, seizure, coma) are the results of brain glucose deprivation itself. Glycemic thresholds for symptoms of hypoglycemia shift to lower plasma glucose concentrations following recent episodes of hypoglycemia, leading to the syndrome of hypoglycemia unawareness--loss of the warning symptoms of developing hypoglycemia. Thus, patients with recurrent hypoglycemia (e.g., those with tightly controlled diabetes or with an insulinoma) often tolerate abnormally low plasma glucose concentrations without symptoms.


Diabetes | 1989

Hypoglycemia in IDDM

Philip E. Cryer; Christian Binder; Geremia B. Bolli; Alan D. Cherrington; Edwin A M Gale; John E. Gerich; Robert S. Sherwin

Hypoglycemia causes substantial morbidity and some mortality in insulin-dependent diabetes mellitus (IDDM). It is often the limiting factor in attempts to achieve euglycemia. The prevention or correction of hypoglycemia normally involves both dissipation of insulin and activation of glucose counterregulatory systems. Among the latter, glucagon plays a primary role initially, whereas epinephrine is not critical, although it becomes critical when glucagon is deficient. Growth hormone and cortisol play demonstrable roles in recovery from prolonged hypoglycemia. Glucose autoregulation may be involved in defense against severe hypoglycemia. With respect to pathophysiology, counterregulatory systems are involved in at least five clinical glucoregulatory syndromes. Defective glucose counterregulation is associated with, and best attributed to, combined deficiencies of the glucagon and epinephrine responses to plasma glucose decrements. Almost assuredly in concert with hypoglycemia unawareness, it results in a markedly increased frequency of severe hypoglycemia, at least during intensive therapy of IDDM. Defined as a night to morning increase in plasma glucose concentration, the dawn phenomenon is thought to result from dissipation of insulin plus the effects of nocturnal growth hormone secretion. Despite a sound rationale, the clinical relevance of the Somogyi phenomenon has been recently questioned. The clinical impression of altered glycemie thresholds for symptoms, i.e., patients with poorly controlled IDDM suffer symptoms of hypoglycemia at relatively high plasma glucose levels, whereas those with very well-controlled IDDM often tolerate subnormal glucose levels, has received experimental support. Clearly, hypoglycemia in IDDM is a problem that needs to be solved. Numerous issues need to be addressed through both basic and clinical research. Fundamentally, pending the prevention or cure of IDDM, we must learn to deliver insulin in a much more physiological fashion or to prevent, correct, or compensate for compromised glucose counterregulation if we are to achieve euglycemia safely in most patients with IDDM.


American Journal of Cardiology | 1988

Left ventricular dysfunction after prolonged strenuous exercise in healthy subjects

D. R. Seals; Marc A. Rogers; James M. Hagberg; Chikashi Yamamoto; Philip E. Cryer; Ali A. Ehsani

To determine whether depressed left ventricular (LV) contractile function can occur after prolonged and strenuous exercise, 12 healthy men, 26 +/- 1 years old (mean +/- standard error of the mean) were studied. The subjects exercised on a treadmill at 69 +/- 1% of maximal O2 uptake until exhaustion (170 +/- 10 minutes). Hemodynamic variables were measured before and 10 minutes after exhausting exercise. Baseline systolic blood pressure decreased from 124 +/- 2 to 113 +/- 3 mm Hg (p less than 0.001) after exhausting exercise. LV end-diastolic diameter, measured by echocardiography, decreased from 51 +/- 1.0 to 47 +/- 1.0 mm (p less than 0.005) but LV end-systolic diameter did not change (34 +/- 1.0 vs 34 +/- 1.0 mm). Both LV fractional shortening and the mean velocity of circumferential fiber shortening decreased (33 +/- 1 vs 28 +/- 1%; p less than 0.01 and 1.09 +/- 0.4 vs 0.97 +/- 0.05 circ/s; p less than 0.025) despite a lower end-systolic wall stress (sigma es = 88 +/- 4 vs 82 +/- 5, X 10(3) dynes/cm2; p less than 0.05) after prolonged exhausting exercise. A repeat bout of exercise of the same intensity but brief in duration (10 minutes) resulted in increases in LV fractional shortening (p less than 0.001) and mean velocity of circumferential fiber shortening (p less than 0.001), and a decrease in LV end-diastolic diameter (50 +/- 1.0 to 48 +/- 1.0 mm; p less than 0.05) at heart rates comparable to those attained after prolonged exhausting exercise. The results suggest that prolonged strenuous exercise may result in impaired LV function in healthy young subjects.


Endocrinology and Metabolism Clinics of North America | 2010

Hypoglycemia in Type 1 Diabetes Mellitus

Philip E. Cryer

Iatrogenic hypoglycemia, typically the result of the interplay of therapeutic hyperinsulinemia and compromised defenses resulting in hypoglycemia-associated autonomic failure (HAAF) in diabetes, is a problem for people with type 1 diabetes mellitus (T1DM). It causes recurrent morbidity is sometimes fatal, leads to recurrent hypoglycemia, and precludes euglycemia over a lifetime of T1DM. Risk factors include those that result in relative or absolute insulin excess and those indicative of HAAF in diabetes. Elimination of hypoglycemia from the lives of people with T1DM will likely be accomplished by new treatment methods that provide plasma glucose-regulated insulin replacement or secretion.


Diabetologia | 2009

Preventing hypoglycaemia: what is the appropriate glucose alert value?

Philip E. Cryer

Contrary to the assertions of Swinnen et al. [1], Frier [2] and Amiel et al. [3], the American Diabetes Association (ADA) Workgroup on Hypoglycemia [4] defined hypoglycaemia in diabetes as ‘all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm’. It is not possible to state a single plasma glucose concentration that defines hypoglycaemia because the glycaemic thresholds for responses to falling glucose levels, including those for symptoms, are dynamic. The ADA Workgroup recommended that people with diabetes (implicitly those with insulin secretagogueor insulin-treated diabetes) should become concerned about the possibility of developing hypoglycaemia at a self-monitored plasma glucose concentration of ≤3.9 mmol/l (70 mg/dl) [4]. Given the limited accuracy of monitoring devices [5], this conservative lower limit for individuals with diabetes approximates the lower limit of the postabsorptive plasma glucose concentration range (approximately 3.9–6.1 mmol/l [70–110 mg/dl] [6]) and the glycaemic threshold for activation of glucose counter-regulatory systems (approximately 3.6–3.9 mmol/l [65–70 mg/dl] [6–9]), and is low enough to cause reduced glucose counter-regulatory responses to subsequent hypoglycaemia [10] in non-diabetic individuals. It is higher than the glucose levels required to produce symptoms in non-diabetic individuals (approximately 2.8–3.1 mmol/l [50–55 mg/dl] [6–9]) and substantially higher than those that do so in people with well-controlled diabetes [11], although individuals with poorly controlled diabetes sometimes have symptoms at higher glucose levels [11, 12]. Thus, the recommended glucose alert level of ≤3.9 mmol/l (70 mg/dl) is data-driven, generally gives the patient time to take action to prevent a clinical hypoglycaemic episode, and provides some margin for the limited accuracy of glucose monitoring devices at low plasma glucose concentrations [5]. The ADA Workgroup-recommended alert value does not, of course, mean that people with diabetes should always self-treat at an estimated plasma glucose concentration of ≤3.9 mmol/l (70 mg/dl). Rather, it suggests that they should consider actions ranging from repeating the measurement in the short term, through behavioural changes such as avoiding exercise or driving, to carbohydrate ingestion and adjustments of the treatment regimen. The data reported by Swinnen et al. [1] nicely document that a higher plasma glucose cut-off value increases the percentage of affected patients and increases the proportion of patients who are asymptomatic; but those are predictable findings. Their data also indicate that a higher cut-off value Diabetologia (2009) 52:35–37 DOI 10.1007/s00125-008-1205-7


Diabetes Care | 1993

Glycemic Actions of Alanine and Terbutaline in IDDM

Brian V Wiethop; Philip E. Cryer

OBJECTIVE To test the hypothesis that the amino acid Ala and the beta 2-adrenergic agonist terbutaline raise plasma glucose concentrations substantially, and do so through different mechanisms, in IDDM patients. RESEARCH DESIGN AND METHODS We administered these (Ala: 20 and 40 g, orally; terbutaline: 2.5 and 5.0 mg orally and 0.25 mg subcutaneously) and placebos in random sequence to 6 nondiabetic subjects and 6 insulin-infused, initially euglycemic IDDM patients, each studied on six different occasions. Inhaled terbutaline, 0.4 mg, was also tested on a seventh occasion in IDDM patients. RESULTS Ala administration raised plasma glucagon (P = 0.0219), C-peptide (P = 0.0014), and insulin (P = 0.0094), with no significant change in plasma glucose, in nondiabetic subjects. In patients with IDDM it raised glucagon (P = 0.0001), but not C-peptide or insulin, and plasma glucose rose to 8.3 ± 0.3 (Ala 20 g, P = 0.0006) and 10.0 ± 1.0 mM (Ala 40 g, P = 0.0094). Catecholamine levels were unchanged. Terbutaline ingestion raised plasma glucose minimally (e.g., to 6.3 ± 0.3 mM, P = 0.0133) in nondiabetic subjects but substantially, to 10.2 ± 1.0 (terbutaline 2.5 mg, P = 0.0078) and 14.0 ± 0.6 mM (terbutaline 5.0 mg, P = 0.0001), in IDDM patients; subcutaneous terbutaline raised plasma glucose (to a peak of 10.3 ± 0.7 mM, P = 0.0017) with an initial effect within 10 min, but inhaled terbutaline did so more slowly. In addition to its direct glycemic actions, terbutaline stimulated sympathetic neural norepinephrine release (P = 0.0151) and increased nonesterified fatty acid levels (P = 0.0104), potential indirect glycemic actions. Glucagon levels were unchanged; insulin levels increased in the nondiabetic subjects. CONCLUSIONS These data demonstrate substantial glycemic responses to Ala and terbutaline, through different mechanisms, in IDDM patients. Thus, Ala and terbutaline represent potential new approaches to the treatment, and perhaps the prevention, of iatrogenic hypoglycemia in IDDM.

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Julio V. Santiago

Washington University in St. Louis

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Neil H. White

Washington University in St. Louis

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Agbani Dagogo-Jack

Washington University in St. Louis

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Ali A. Ehsani

Washington University in St. Louis

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Amy L. Alderson

Washington University in St. Louis

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Brian V Wiethop

Washington University in St. Louis

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Charles Kilo

Washington University in St. Louis

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Chikashi Yamamoto

Washington University in St. Louis

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