Activation of adenylate cyclase in renal medulla by bovine growth hormone. An artifact attributable to vasopressin.

The effect of bovine growth hormone on adenylate cyclase activity was studied in bovine and rat renal medulla. Highly purified growth hormone (lot B1003A) increased adenylate cyclase activity in plasma membranes from bovine renal medulla from 132+/-6 pmol cyclic AMP formed/mg protein per 10 min to 364+/-10 pmol cyclic AMP formed/mg protein per 10 min. Similar results were seen with homogenates of rat renal medulla. The minimum effective concentration of bovine growth hormone required to activate adenylate cyclase was 0.5 mug/ml and maximum activation was detected at 500 mug/ml. The amount of vasopressin determined by radioimmunoassay to contaminate the growth hormone caused an increase in adenylate cyclase activity comparable to that of the corresponding concentration of growth hormone that was tested. Dialysis of growth hormone and vasopressin resulted in parallel reductions in the effect of each hormone on adenylate cyclase activity. Similarly, both growth hormone and vasopressin produced increases in short circuit current in isolated toad bladders but these effects were not detectable after dialysis of the hormones. In contrast, the effect of growth hormone on the uptake of 35SO2-4 by cartilage from hypophysectomized rats was not decreased after dialysis. These results indicate that available preparations of growth hormone are contaminated by small but physiologically significant amounts of vasopressin and that the activation of adenylate cyclase activity in renal medulla in response to growth hormone can be explained by this contamination rather than by an effect of growth hormone per se.

Exogenous, but not endogenous, cyclic GMP reduces hepatic pyruvate kinase activity.

We investigated the effects of exogenous cyclic GMP and stimulants of endogenous cyclic GMP accumulation on L-form (hepatic) pyruvate kinase (ATP: pyruvate 2-O-phosphotransferase, EC 2.7.1.40) activity in isolated rat hepatocytes. Exogenous cyclic GMP (200 muM) reduced pyruvate kinase activity, but was less potent than exogenous cyclic AMP (50 muM) (Ki congruent to 120 muM vs. 30 muM, respectively), had a slower onset of action (1.0 vs. 0.3 min, respectively) and a less rapid maximal effect (5.0 vs. 1.0 min, respectively). Similar results were noted with dibutyryl cyclic GMP or dibutyryl cyclic AMP. 1.0 muM acetylcholine increased cyclic GMP concentrations in isolated hepatocytes from 233 +/- 16 to 447 +/- 3 pmol/g cell protein (P less than 0.001), but did not alter pyruvate kinase activity. Similar results were noted with carbamylcholine, NaN3 or acetylcholine plus eserine sulfate. The results suggest a differential effect of exogenous vs. endogenous cyclic GMP on L-form pyruvate kinase activity, and question the physiological relevance of observations with exogenous cyclic GMP in this system.

Effect of adrenergic agents on postgastrectomy hypoglycemia.

Reactive hypoglycemia was documented in ten postgastrectomy patients by a control oral glucose tolerance test (OGTT). Nine patients experienced nausea, flushing, and fatigue during the first hour of the test. Neuroglycopenic or adrenergic symptoms of hypoglycemia occurred in eight patients two to five hours after oral glucose. The oral administration of phenylephrine elixir, 15 mg., thirty minutes before a repeat OGTT, significantly raised thelowest plasma glucose from 37.5 +/- 2.8 mg./dl. to 45.2 +/- 3.8 mg./dl. (p less than 0.05) but did not affect the occurrence of either the early or the late symptoms. In contrast, propranolol, 10 mg., raised the lowest plasma glucose from 37.5 +/- 2.8 mg./dl. to 57 +/- 5.2 mg./dl. (p less than 0.02) and prevented the occurrence of early and late symptoms. Neither peak nor total plasma insulin levels were affected by either drug. The rate of glucose utilization, as determined by intravenous glucose tolerance tests, did not significantly change after the oral administration of either drug. It is concluded that propranolol ameliorated the symptoms and chemical hypoglycemia after oral glucose and merits more detailed study as a long-term therapy for this disorder.

Long-term follow-up of diabetic patients using insulin infusion pumps. Considerations for future clinical application.

Current debate about the use of insulin infusion pumps in the treatment of diabetes mellitus is partly attributable to a lack of available data about the long-term course of patients who use pumps. We evaluated the course of our first 20 patients treated with insulin infusion pumps. Two or more years after the inception of therapy, only half of these patients were still using the insulin infusion pump. Psychosocial stresses, which affected glycemic control, were identified retrospectively in a majority of patients, but were not appreciated when pump therapy was initiated, despite our best attempts to do so. Mean hemoglobin A1 levels decreased significantly for the entire group and for the subgroup that did not discontinue pump therapy. These results suggest that insulin pump programs must have the resources to provide appropriate support for all candidates, including unsuitable candidates, who present for treatment with insulin infusion pumps.

Bedside capillary glucose monitoring in the general hospital.

We assessed the accuracy and reliability of capillary glucose monitoring (CGM) for 20 hospitalized patients as an alternative to repeated venipunctures for laboratory blood glucose (LBG) determination. A total of 330 pairs of observations was obtained. Pearson correlation between patient estimates using Chemstrip bG and the laboratory glucose-oxidase method was 0.87. The mean LBG determination was 197 +/- 5 mg/dl compared with 176.4 +/- 4.3 mg/dl for patient CGM estimates. The mean deviation was 17.6 +/- 2.9 mg/dl or 8.9%, which is well within the 20% range that is generally accepted as sufficiently accurate. Certain individual patients may require relatively more instruction and supervision to reliably carry out these measurements. These patients may represent 10-25% of all diabetic patients. Neither age nor years of schooling is a useful index to identify these patients. Therefore, we suggest as a routine that 10 or more CGM be checked against simultaneous LBG to confirm accuracy before relying on bedside CGM estimates alone in managing the hospitalized patient. Patients who can carry out CGM accurately may be managed with CGM alone.

Diabetes in Kentucky.

A state diabetes commission and university diabetes program in Kentucky jointly studied the social and economic impact of diabetes mellitus and its complications on the Commonwealth. This investigation revealed that diabetes was a more serious public health problem than previously supposed. Active, diagnosed diabetes afflicts 4.4% Kentucky's population. Less severe clinical and "borderline" forms of diabetes affect an additional 2.4%. Diabetes is especially prevalent in Appalachian regions and in rural, Western Kentucky. In contrast, its prevalence in Lexington, the second-largest city, is 2.7%, similar to the current, estimated national prevalence. Diabetes is the leading cause of hospitalization by disease, and costs approximately $98,800,000 to $135,000,000. Previous estimates of these social and economic losses were lower, partly because they failed to account for the impact of diabetic complications. An average of 5.23% of all hospitalized Kentuckians have diabetes. Specific services for diabetes care, including organized patient education programs, social or psychological counseling, and preventive foot care, were offered by less than 8% of accredited Kentucky hospitals. This study demonstrates the disparity between need and available services, particularly preventive services, for diabetes care in the health care system.

Readability of self-care instructional pamphlets for diabetic patients.

The readability of written instructional materials for diabetic patients is an important consideration in their use. We assessed the readability of six commonly used patient teaching guides on diabetic self-care. In addition, two pamphlets developed by our program for diabetic patients with fifth to tenth grade reading ability were also studied as controls. The difficulty of reading each pamphlet was estimated by a novel computer program which simultaneously measures readability by seven accepted formulas. The scores derived by each formula are expressed individually, in terms of grade level difficulty, and then computed to obtain a composite mean score for each text. The composite mean scores obtained are highly reliable (a = 0.95). The six commercial pamphlets were estimated to have reading difficulty levels ranging from 5.3 to 14.1 grades. A primary factor that contributed to reading difficulty was the frequent use of polysyllabic words, including technical words. Certain individual test scores, not judged to be out of range, deviated from the mean composite scores by as much as 41.2%. The two pamphlets designed by the Kentucky Diabetes Program had composite reading difficulties of 7.5 and 8.2 grade levels, respectively. These data suggest that the use of systematic readability analysis should be carried out and reported for patient instructional material. This assessment should be carried out by multiple formulas to produce a more representative index of reading difficulty than the application of a single test.

Phospholipid and glutamic acid decarboxylase autoantibodies in diabetic neuropathy.

OBJECTIVE: To determine the prevalence and significance of phospholipid autoantibodies (PLAs) and glutamic acid decarboxylase (GAD) autoantibodies in the circulation of normal patients and diabetic patients with and without neuropathy. RESEARCH DESIGN AND METHODS: We measured PLAs in a total of 78 patients (a diabetic group with somatic or autonomic neuropathy [n = 40] another group without neuropathy [n = 38]), and GAD autoantibodies in a subset of 22 patients. RESULTS: PLAs are found in 2% of the general population. We found PLAs in 32% of the diabetic population without neuropathy, in 88% of those with neuropathy, in 55% of those with retinopathy, and in 25% of those with established nephropathy. The frequencies of immunoglobulins in the neuropathic group were: IgG = 78%, IgM = 33%, and IgA = 23%. There was no correlation between PLAs and microalbuminuria, macrovascular disease, fibrinogen, duration of diabetes, or neuropathy, but there was a strong correlation with total neuropathy score. Sera with high PLA IgG titers bound to the surface of neuroblastoma cells and inhibited cell growth. Antibodies to GAD65 were present in 32% and to GAD67 in 0% of patients. No titers of GAD65, GAD67, or the GAD65 ratio were associated with the degree of neuropathy of the presence of PLAs. CONCLUSIONS: PLAs occur frequently in the sera of patients with diabetes and correlate with the extent of neuropathy, suggesting a role for PLAs in the etiology thereof. The measurement of PLAs may constitute a marker for ongoing damage to nerves.

Normal gestation and diminished androgen responsiveness in an untreated patient with 21-hydroxylase deficiency.

A 22-year-old woman with 21-hydroxylase deficiency but minimal clinical evidence of androgenization was studied. She had conceived twice and had borne a normal male infant without therapy of any kind. The diagnosis of 21-hydroxylase deficiency was substantiated by the findings of 17-ketosteroid and pregnanetriol excretions of 18.1 and 8.1 mg/24 hours, respectively. Adequate basal compensation was indicated by a fasting plasma cortisol of 17.5 mug/dl. Plasma ACTH (207 pg/ml), testosterone (216 ng/dl) delta4-androstenedione (649 mg/dl), progesterone (249 ng/dl) and 17alpha-hydroxyprogesterone (4820 ng/dl) were all significantly elevated.

Thyroid function and growth hormone secretion in amitriptyline-treated depression.

The authors studied changes in indices of thyroid function prospectively in a group of 11 patients given amitriptyline to treat depression. The drug caused no significant alteration in these indices, but scores on the Hamilton Depression Rating Scale improved significantly. In another group of subjects with depression, the stimulation of growth hormone secretion by L-dopa was unaffected by amitriptyline therapy.

Clinical and metabolic aspects of glucagonoma.

The features of 41 proven or suspected cases of pancreatic glucagonoma and one possible case of renal glucagonoma have been reviewed. Glucagonoma is one form of islet cell neoplasm and involves pancreatic alpha cells. It may occur more frequently in women and is more likely to be malignant than insulinoma. Patients may present with glucose intolerance, an erythematous, eczematous dermatitis, glossitis, stomatitis, vaginitis and unexplained weight loss. Anemia, hypoproteinemia, hypoaminoacidemia and hypolipidemia may also be present. Malignant glucagonoma metastasizes frequently to liver. An evaluation for possible glucagonoma may be considered in a patient with the characteristic eczematous dermatitis, glossitis or stomatitis and glucose intolerance, an unusual or atypical history of diabetes mellitus, or hepatomegaly with other characteristics of glucagonoma. Initial evaluation may include measurement of fasting plasma glucagon concentration, and an oral glucose tolerance test with measurements of plasma glucose and glucagon levels. Extreme fasting hyperglucagonemia, and a paradoxical rise in plasma glucagon concentrations after glucose ingestion should strongly suggest the presence of glucagonoma. Radiographic demonstration of pancreatic glucagonoma is best carried out by celiac arteriography. Surgical excision of the tumor is the treatment of choice. Nonresectable lesions may respond to chemotherapy with streptozotocin. Treatment for the various dermatologic or metabolic complications of glucagonoma which include glucose intolerance, hypoproteinemia, hypocholesterolemia and anemia may not be satisfactory. Glucose intolerance is usually mild and may be adequately treated with dietary or insulin therapy. Rarely, glucagonoma with massive destruction of the pancreas or other factors may induce severe glucose intolerance. In contrast, the anemia, skin rash, and hypoproteinemia do not respond to conservative therapies tested thus far. Glucagonoma is a model for studying the importance of glucagon in causing the hyperglycemia of diabetes mellitus. Study of patients with glucagonoma does suggest that glucagon has some role in the etiology of hyperglycemia in diabetic states; however, as in studies on diabetes, investigations on glucagonoma do not demonstrate that glucagon has a primary role in producing severe glucose intolerance.

Alimentary hypoglycemia: a new appraisal.

The clinical evaluation and the results of oral glucose tolerance tests in patients with alimentary hypoglycemia, reported previously or studied as part of our group of 24 patients with this disorder, suggest that alimentary hypoglycemia may differ from other reactive hypoglycemias in clinical presentation and importance. Unlike other reactive hypoglycemias, alimentary hypoglycemia may be associated with severe or permanent neuropsychiatric complications. Subtle, "neuroglycopenic" symptoms of hypoglycemia may occur, instead of "typical," "adrenergic" symptoms. Glucose ingestion, by causing early hyperglycemia and provoking the release of insulinotropic enteric hormones appears responsible for this disorder. Therefore, therapy with diets low in simple sugar, but unrestricted in complex carbohydrate and fiber are now advocated.

Uncontrolled diabetes mellitus and hyperglucagonemia associated with an islet cell carcinoma.

A 53 year old woman presented with diabetes mellitus, hyperglucagonemia (600 to 1,500 pg/ml), clinical hyperparathyroidism and an abdominal mass diagnosed on biopsy as an islet cell carcinoma. Glucagon content of the tumor was 0.78 mug/g wet weight. Hourly blood samples during a 24 hour period revealed a direct correlation between plasma glucose and glucagon. The oral administration of glucose paradoxically increased whereas the intravenous administration decreased plasma glucagon. Circulating glucagon levels were markedly increased with arginine and epinephrine infusion. Both short- and long-term administration of alpha adrenergic blockade depressed the glucagon response to epinephrine infusion. In contrast, long-term alpha adrenergic blockade increased glucagon secretion despite improved glucose tolerance during a second 24 hour study. Although the patient demonstrated overt clinical and chemical findings of hyperparathyroidism, parathyroid hormone (PTH) was not detected in her plasma. The pattern of tumor growth was consistent with an origin from pancreatic islets. We conclude that (1) the tumor was responsive to physiologic stimuli known to affect glucagon secretion; (2) elevations of plasma glucagon levels with oral and dietary glucose suggest regulation of secretion by intestinal factors; and (3) improvement of glucose tolerance with alpha adrenergic blockade may be related to increased insulin secretion.

Clinical characteristics of diabetic patients with serious pedal infections.

The clinical characteristics of 55 diabetic patients referred for treatment of serious pedal infections were surveyed. These patients had been infected for 22.5 +/- 5.0 weeks prior to referral. A majority had received therapy with oral antibiotics and approximately one third had received no antibiotic therapy. The average age of the patients was 53.5 years; average duration of disease, 18 years; and mean weight, 135% of ideal. All had poor glycemic control, as judged by hemoglobin A1c determinations. The patients had a high prevalence of diabetic complications, particularly peripheral neuropathy and nephropathy. Approximately 69% were hypertensive. Although their corrected ESRs were elevated, mean total WBC counts were not. A majority of the patients had zinc deficiency. Most of their infections involved multiple organisms, particularly staphylococcus species, enterococcus, and gram-negative aerobes. These observations suggest that the clinical characteristics of these patients in part explain the difficult nature of their infections and argue the need for early, aggressive antibiotic therapy.

New concepts in managing diabetic foot infections.

Recent enhanced attention to diabetic foot infection--in both clinical care and research--has yielded a modified picture of this disorder. It suggests that certain diabetic patients may have important risk factors for the development of infection, and further, infections in these patients may not have the same clinical characteristics as the soft tissue or bony infections found in nondiabetic subjects. Treatment of diabetic patients should therefore be modified to conform to the particular characteristics of their infections.