R. Philip Eaton

Post-Prandial Blood Glucose Determination by Quantitative Mid-Infrared Spectroscopy

The multivariate calibration method of partial least-squares (PLS) was applied to the mid-infrared spectra of whole blood for quantitatively determining blood glucose concentrations. Separate calibration models were developed on the basis of spectra of whole blood obtained from six diabetic subjects from either in vitro glucose-supplemented blood or blood obtained from the same subjects in the post-prandial state during meal tolerance tests. The cross-validated PLS calibrations yielded average errors in glucose concentration of 11 and 13 mg/dL, respectively. It is desirable to use the calibration models based on the in vitro glucose-supplemented blood for determining glucose concentrations in unknown blood samples. However, when these multivariate calibration models based upon in vitro blood spectra were applied to the spectra of the postprandial blood samples, a subject-dependent concentration bias was observed. The source of this bias was not identified, but when the glucose determinations were corrected for the bias, average concentration errors were found to be 14 mg/dL. Changes in spectrometer design or calibrations based on large numbers of subjects are expected to eliminate the presence of this bias. If these measures do not succeed in eliminating the bias, then methods are demonstrated that significantly reduce the bias while retaining the sensitive outlier detection capabilities of the PLS methods. These latter methods require that the infrared spectrum and reference glucose levels be obtained from a single blood sample from each subject.

The kinetics of peritoneal insulin absorption

This study examined the relationship between the delivery of insulin into the peritoneal space and its absorption into the peripheral circulation. Studies were performed in conscious dogs receiving somatostatin (5.0 microgram/min) to suppress endogenous insulin secretion, and intravenous glucose (50 mg/min) to prevent hypoglycemia. The biologic effectiveness of the absorbed insulin was determined by its hypoglycemic effect. The possibility of direct absorption of insulin into the portal circulation from the peritoneal space in anesthetized, portal vein-catheterized dogs was examined with radiolabeled I125 insulin. Our results suggest that absorption of insulin from the peritoneal space is volume, concentration, and time-dependent. Maximal absorption of insulin was observed at 50 min when 1.92 U of insulin in a volume of 3 ml was infused intraperitoneally over 30 min. More rapid absorption was observed at 30 min when this quantity of insulin was given in a 1-min intraperitoneal bolus, compared to 30 min of intraperitoneal infusion. Least rapid absorption of insulin followed the delivery of 1.92 U of insulin in a volume of 15 ml. Intermediate absorption of insulin was observed at 40 min when the 1.92 U was delivered in a volume of 0.6 ml. Peripheral intravenous insulin delivery of 1.92 U reached a maximal plasma concentration at 20 min, which was more than three times the concentration observed with intraperitoneal insulin. Isotopic tracer studies, in which radioiodinated insulin was placed into the peritoneal space in anesthetized dogs, demonstrated greater radioactivity in the portal vein than in the aorta throughout a 30-min observation period. These studies demonstrate that intraperitoneal administration of insulin results in absorption of insulin which is volume, concentration, and time-dependent. Thus, the peritoneal space may be an appropriate site for insulin delivery through a transcutaneous catheter.

The Etiology of Incapacitating, Brittle Diabetes

Incapacitated brittle diabetic subjects are a small subset of insulin-dependent diabetic individuals who are unable to maintain a normal lifestyle because of frequent disruptions secondary to severe hypergly-cernie and/or hypoglycemic episodes. Thirty incapacitated patients were referred for evaluation because the cause of their diabetic instability could not be determined by their personal physicians despite extensive patient training in correct diabetes management, frequent hospitalizations for observation, and multiple diagnostic testing. From the 30 patients, a diagnostic algorithm was developed (described in the companion article) from which the etiology of brittle diabetes could be established in 29. This article provides the clinical characteristics of each of the 30 patients, a description of the etiologie categories of brittle diabetes, and the clinical follow-up from the time that the etiologie diagnosis was established and treatment recommended. Although extensive medical records were sent with each patient, without prospective objective testing under rigidly controlled conditions, the correct etiologie diagnosis would not have been evident from the clinical presentation of the patient. Of equal importance in identifying the etiology of brittle diabetes was the acceptance and cooperation of the referring physician in providing close follow-up and repeat insulin challenge testing when necessary. In this referred patient population, eight subjects had factitious disease, eight were malingering, seven had communication deficits, two had gastroparesis, two had systemic insulin resistance, two had miscellaneous causes of brittle diabetes, and one patient remained undiagnosed. Using a prospective algorithmic approach to determine the etiology of brittle diabetes, not only is the cause of diabetic instability almost always identifiable, but a significant improvement in lifestyle is achieved in greater than 50% of the incapacitated individuals.

Thyrotoxicosis and Periodic Paralysis: Improvement with Beta Blockade

Excerpt Periodic paralysis associated with thyrotoxicosis was observed in three unrelated American Indian males and one white male of Russian-Jewish descent. Hypokalemia was observed in all patient...

Diabetic Neuropathy: Structural Analysis of Nerve Hydration by Magnetic Resonance Spectroscopy

The water content of the sural nerve of diabetic patients was quantitatively defined by magnetic resonance proton imaging as a putative reflection of activity of the aldose-reductase pathway. Thirty-nine patients were evaluated, comparing group A, symptomatic diabetic men with sensory neuropathy; group B, similarly symptomatic diabetic men treated with aldose-reductase inhibition; group C, neurologically asymptomatic diabetic men; and group D, control nondiabetic men. Marked increase in hydration of the sural nerve was seen in more than half of the symptomatic diabetic patients. Two of 11 neurologically asymptomatic diabetics had increased nerve hydration, suggesting a presymptomatic alteration of the nerve. Symptomatic diabetics treated with aldose-reductase inhibitors had normal nerve water levels. Increased level of peripheral nerve water represents a new finding in diabetes mellitus. It seems to be related to aldose-reductase activity, involved in the development of neuropathy, and similar to events that occur in other target tissue in human diabetes.

Effect of clofibrate on arginine-stimulated glucagon and insulin secretion in man

Insulin and glucagon have been reported to have opposing effects upon the mechanisms regulating serum triglyceride concentration. Glucagon in excess of insulin will lower serum lipids in man. In the present studies, we have examined the possibility that a change in glucagon and insulin regulation might contribute to the hypolipemic action of the drug clofibrate. Control insulin and glucagon secretion were evaluated in 24 normal subjects by intravenous arginine infusion, which resulted in a prompt rise in both serum immunoreactive insulin and glucagon concentration. During the maximum rise in concentration of these hormones, plasma triglyceride concentration was acutely reduced from basal levels of 104 ± 6 mg100 ml to 75 ± 5 mg100 ml (p ≤ 0.001). Following 7 days of clofibrate therapy, basal plasma triglyceride concentration attained a new mean level of 78 ± 5 mg100 ml, while basal insulin and glucagon concentrations remained unchanged. However, arginine infusion now resulted in a reduction of the insulin secretory response to 56% of the preclofibrate studies with an associated normal glucagon secretory response. Serum triglyceride concentration was further reduced during arginine infusion to 46 ± 3 mg100 ml, demonstrating this minimum level as maximum plasma glucagon levels were attained, representing an excess of this hormone relative to the reduced insulin concentration. These observations are consistent with an effect of clofibrate on the hormonal regulation of triglyceride physiology in man. Glucose tolerance was unimpaired by clofibrate therapy in these normal subjects, in spite of an apparent reduction in glucose-stimulated insulin secretion.

The role of glucagon in the regulation of plasma lipids

The role of glucagon in regulating plasma lipid concentrations (nonesterified fatty acids, ketone bodies, and triglycerides) is reviewed. The effects of glucagon-induced insulin secretion upon this lipid regulation are discussed that may resolve conflicting reports in the literature are resolved. In addition, the unresolved problem concerning the pharmacologic versus physiologic effects of glucagon is stressed. Glucagons role in stimulating lipolysis at the adipocyte serves two important functions. First, it provides plasma nonesterified fatty acids for energy metabolism and secondly, it ensures substrate for hepatic ketogenesis. In vitro, glucagons lipolytic activity has been consistently observed, but in vivo, this activity has sometimes been obscured by the effects of glucagon-induced insulin secretion. Frequently, a biphasic response has been reported in which a direct lipolytic response is followed by a glucagon-induced insulin suppression of plasma nonesterified fatty acid concentration. When the glucagon-induced insulin secretion has been controlled by various in vivo techniques, glucagons lipolytic activity in vivo has frequently been demonstrable. In the 1960s, in vitro liver perfusion experiments demonstrated that glucagon enhanced hepatic ketogenesis independent of glucagons lipolytic activity. However, this direct effect of glucagon on the hepatocyte was not universally accepted because of conflicting reports in the literature. Failure to observe an in vitro ketogenic effect of the hormone in some studies may have been due to suboptimal experimental conditions. Certain factors are now known to influence the ketogenic response, such as the concentration of fatty acids in the media and the nutritional status of the animal. Under optimal in vitro conditions with liver preparations from fed animals, the ketogenic response to physiologic concentrations of glucagon has been demonstrated. However, further study is necessary to define the quantitative ketogenic role of the hormone. In spite of this early in vitro work, glucagon was not definitely shown to be ketogenic in vivo (independent of fatty acid availability) both in the rat and in diabetic man until 1975. Since these observations, several reports have confirmed the ketogenic action of glucagon in vivo by direct hepatic catheterization experiments. Glucagons role in decreasing hepatic triglyceride synthesis and secretion in vitro has been repeatedly shown but the mechanism is unresolved. This lipid regulatory action of glucagon has been more difficult to demonstrate in vivo because of the many variables that affect triglyceride synthesis. Under specific experimental conditions, however, glucagon has been shown to decrease plasma triglyceride concentration in man at both physiologic and pharmacologic concentrations. Hepatic catheterization experiments have also confirmed this effect in man. The regulation of lipids by glucagon fits well into its role as a stress hormone...

Effects of insulin infusion on plasma phosphate in diabetic patients.

A clinical association between insulin therapy and hypophosphatemia has frequently been made but a dose-response relationship has not been reported. Furthermore, the rapidity by which hypophosphatemia may be induced following an increment in plasma-free insulin concentration is not well defined. Therefore this study compared the effects of different rates of insulin infusion on the changes in plasma phosphate concentration in ketotic, hyperglycemic diabetic man. Sixteen prospective studies were performed in four insulin-dependent ketotic diabetic subjects. Insulin was infused according to one of four different protocols: high dose (1.0 U/kg/hr), low dose (0.1 U/kg/hr), very low dose (0.01 U/kg/hr) and control (saline only). Plasma phosphate, glucose, and free insulin concentrations were measured sequentially during the 60 min infusion periods. We observed that plasma phosphate concentrations declined significantly only with low-dose and high-dose insulin infusions. The magnitude and rapidity of fall of the mean phosphate concentration were greatest with high-dose insulin infusion. Significant hypophosphatemia can be observed within 30 min following the onset of insulin therapy.

Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate

OBJECTIVE To assess the efficacy of estrogen antagonist therapy on the function of the hypothalamic-pituitary-testicular axis in a young male runner with significant morbidity attributable to idiopathic hypogonadotropic hypogonadism. DESIGN An uncontrolled case study. SETTING The outpatient endocrinology clinic of a university tertiary referral center. PATIENT(S) A 29-year-old male who has run 50 to 90 miles per week since 15 years of age and who presented with a pelvic stress fracture, markedly decreased bone mineral density, and symptomatic hypogonadotropic hypogonadism. INTERVENTION(S) Clomiphene citrate (CC) at doses up to 50 mg two times per day over a 5-month period. MAIN OUTCOME MEASURE(S) Serum concentrations of LH, FSH, and T before and after CC therapy, as well as clinical indicators of gonadal function. RESULT(S) Barely detectable levels of LH and FSH associated with hypogonadal levels of T were restored to the normal range with CC therapy. The patient experienced improved erectile function, increased testicular size and sexual hair growth, and an improved sense of well being. CONCLUSION(S) Exercise-induced hypogonadotropic hypogonadism exists as a clinical entity among male endurance athletes, and CC may provide a safe and effective treatment option for males with debilitating hypogonadism related to endurance exercise.

The effects of altered thyroid status on lipid metabolism in the genetic hyperlipemic zucker rat

Exposure to thyroid hormone (T4) has been known to affect the plasma triglyceride (TG) as well as the plasma cholesterol level, but the mechanisms and degree of response in genetic hyperlipidemic states have not been defined. In the present study, we examined TG secretion and removal in vivo in genetically hyperlipemic Zucker rats maintained in hypothyroid, euthyroid, and hyperthyroid states for 6 weeks. The induction of the hypothyroid state resulted in marked weight loss with reduced food intake, and a parallel reduction in plasma TG concentration, hepatic TG production, and peripheral TG removal. In contrast, a similar degree of weight loss in the hyperthyroid state was associated with increased food intake, but no significant reduction in plasma TG concentration, production, or clearance. The changes in plasma cholesterol concentration in the hyperthyroid state were striking, with a 94% reduction in LDL cholesterol, but only a minimal reduction in the HDL cholesterol level. The hypercholesterolemic state in the Zucker rat. The results suggest that the very low density lipoprotein TG metabolism is influenced by hypothyroid but not the hyperthyroid state in this model of human genetic Type IV hyperlipemia. The primary reduction in LDL relative to HDL in response to thyroxine excess, suggests a therapeutic potential in disorders of genetic hyperlipidemia.