Henry T. Ricketts

Biochemical Studies of “Prediabetes”

Five-hour glucose tolerance (GTT), serum insulin (IRI) response to glucose, glucose tolerance after cortisone (CGTT), tolbutamide tolerance (TTT) with insulin response, free fatty acids (FFA) after fasting and after glucose, blood ketones after fasting, and fractional serum lipids after cortisone were determined in most or all of twenty-five subjects with a strong predisposition to diabetes, twenty-one of them being the offspring of pairs of diabetic parents. Twenty-four healthy subjects with no family history of diabetes served as controls. Although all results except those of the CGTT were within accepted limits of normal, “prediabetics” differed significantly from controls in having higher one-half-hour, one-hour and two-hour blood sugar values and higher IRI levels at one and two hours during GTT, higher blood sugar values at one-half hour, one hour and two hours during CGTT, and smaller and slower depression of blood sugar despite normal insulin response during TTT. No differences in lipid metabolism between the two groups were found except that, surprisingly, the controls had higher FFA after twenty-four-hour fasting than the “prediabetics.” Small but definite deviation in glucose metabolism, and possibly in insulin reponse glucose, remain the most sensitive biochemical indicators to the “prediabetic state,” but their predictive reliability has yet to be ascertained.

The problem of degenerative vascular disease in diabetes

Abstract Diabetes, or some factor related to it, markedly hastens the onset and increases the frequency and severity of arterial and arteriolar sclerosis. In addition, it gives rise to capillary lesions of the renal glomeruli and retina that belong almost exclusively to the diabetic state. Rates of death and disability from these causes are increasing as diabetic patients live longer. Diabetes increases susceptibility to atherosclerosis to a greater extent in women than in men, and the former have a higher incidence of intercapillary glomerulosclerosis but not of retinopathy. Although instances of vascular disease are observed in greater numbers among older patients, its incidence and seriousness in younger patients with long-standing diabetes are striking. Duration of diabetes stands out as the most important single factor, and its effects are greater in younger than in older persons. The parts played by severity and control of diabetes are still in dispute. The best evidence indicates that the highest frequency of advanced lesions occurs in severely diabetic patients with prolonged, heavy glycosuria. It is clear, however, that some patients with mild, well controlled diabetes have manifest vascular lesions while their opposite numbers seem to escape. These inconsistencies lend support to the concept, as yet incapable of proof, that hereditary tendencies may be as important as diabetes itself. The experimental production of both glomerular and retinal lesions with cortisone and corticotropin strengthens the possibility that they have a common pathogenesis in man and raises the question of whether their clinical occurrence is related to adrenal hyperactivity. Evidence on this point is contradictory. Mucopolysaccharides are increased in the blood of diabetic patients with vascular, especially renal, disease but to some extent in those without it and may be related to the pathogenesis of retinopathy and intercapillary glomerulosclerosis. Hyperlipemia in the treated diabetic patient is neither so frequent nor so marked as has been commonly supposed. To the extent that it does exist its association with atherosclerosis is loose and inconstant and in many cases is lacking entirely. Elevated lipid levels in intercapillary glomerulosclerosis are probably a result rather than a cause of the disease. The etiology and pathogenesis of diabetic vascular disease remain obscure.

Electrocardiogram of the Beagle Dog

Summary 1. The taking of the electrocardiogram of the untrained, unanesthetized dog is a practical procedure. 2. In the supine position, the variations in serial tracings are small enough to render the results useful. 3. The electrocardiogram of the normal, young beagle dog is described and a table of normal values is presented.

Spontaneous Diabetes Mellitus in the Dog: An Account of Eight Cases

The literature on spontaneous diabetes in dogs is sparse and is confined almost exclusively to veterinary publications. As summarized recently by Schlotthauer and Millar, it contains reports of 42 cases including eight of their own. Clinical, chemical and pathologic data are sketchy. The frequency of the disease appears to be about one per thousand. It affects females predominantly and occurs from one year of age upward. All cases reported by Schlotthauer and Millar in which necropsy was performed showed either destruction of the pancreas, apparently by inflammatory processes, or, more commonly, extensive abnormalities of the islets of Langerhans. These consisted of diminution in number, hyalinization, fibrosis and, in one case, possibly hydropic degeneration. Those animals with the pancreas destroyed had fatty diarrhea and flatulence in addition to the usual thirst and polyuria. Renal lesions occurred frequently but are incompletely described.

Results and correlations of multistage exercise tests in a group of clinically normal business executives

Abstract Multistage treadmill exercise tests were performed on 91 healthy business executives. Eleven of these subjects exhibited abnormal S-T-segment responses. Although no correlation was found between abnormal exercise responses and the coronary risk factors, the abnormal responders were older and had more abnormalities in the resting ECG. The predictive value of the maximal exercise test will be determined in the long-term follow-up of these individuals.

Diabetes in a Totally Depancreatized Man.

Conclusions (1) The pancreas, or its hormone, insulin, is necessary to life in the human. (2) On the basis of the present case and others previously reported,2-5 the insulin output of the normal human pancreas must be considerably smaller than has been believed and seems to lie in the range of 30 to 50 units per day. Therefore, (3) in diabetic patients requiring more than this amount, an extrainsular factor must be contributing to the diabetic syndrome. (4) The D/N, ratio of from 2.42 to 3.59 indicates that a fasting, depancreatized man deprived of insulin converts protein to carbohydrate at a rate commensurate with that observed in the dog under the same conditions6 or when treated with phloridzin.7

Degradation of insulin by tissue extracts of normal and nephrotic rats.

Summary 1. The insulin-degrading capacity of rat kidney, liver and diaphragm extracts was determined by incubating them with (a) crystalline insulin and observing blood sugar curves in intact rats following intravenous injection of the mixture and (b) I131 insulin and measuring undegraded insulin as represented by TCA precipitable radioactivity. 2. By both measurements, kidney and liver extracts from nephrotic rats were less potent than normal organ extracts in the inactivation of insulin.

Cyclamates and Artificial Sweeteners

Evidence for a carcinogenic effect of cyclamates in rats has been reported in statements by Secretary Robert H. Finch of the United States Department of Health, Education, and Welfare. The law, as embodied in the Delaney Amendment, left the Secretary no choice but to remove these compounds from unrestricted usage. Beverages and medicines containing this sweetener will be withdrawn. Cyclamates will be available only in certain dietary foods and in concentrated liquid and tablet forms as additives for use at the table. They will be sold as nonprescription drugs and labeled as such with the cyclamate content listed. The Secretary further emphasized that cyclamates should be consumed only on the advice of a physician. These statements were made in a series of press releases from October 18 through November 20. The actions taken by the Secretary were based on reports of toxicologic studies in animals, the recommendations of an appointed Medical Advisory Committee, and the law. ^ Cyclamate (cyclohexanesulfanic acid) was discovered in 1944. It is approximately thirty times as sweet as sucrose, in contrast to saccharine which is judged 350 times as sweet. Although saccharine has been known for ninety years, it has not achieved full acceptance as a sugar substitute because of its bitter aftertaste. Cyclamate is available as the sodium or calcium salts. Two of its recently discovered metabolites are cyclohexylamine and dicyclohexylamine. The former substance may be formed in the intestine, and also in stored foods depending on pH alterations and other influences. The marked increase in consumption of cyclamates in the past six years has led to several studies of toxicity. Unfortunately, there has been insufficient time to establish clearly the adverse effects of cyclamate, and, in particular, of its metabolites cyclohexylamine and dicyclohexylamine. There has been suggestion of chromosome breakage in studies of teratogenesis in chick embryos and of mutations in leucocyte cultures. The chromosome effect of immediate importance is, however, the possible production of cancer. Such an effect was reported initially at the University of Wisconsin where bladder cancer was found in mice after implantation of cholesterol-cyclamate pellets. This led to further studies supported by Abbott Laboratories, a producer of cyclamate, which revealed that bladder cancer could be produced with oral cyclamates in rats. The dose producing this effect was 2.5 gm./kg., given over the lifetime of the animal. It was then reported by the HEW Department that similar cancer in rats could be produced with a dose of 400 mg./kg. This latter finding was not available when the initial decision was made to restrict cyclamate usage. It is emphasized by the HEW Department, however, that they have no evidence for increased bladder carcinoma in man after a period of six years of large consumption of cyclamates. Approximately seventeen million pounds of cyclamates were produced in 1968. The largest use, 70 per cent of that produced, was in soft drinks taken mainly by the younger population. Ten per cent was used in prepared foods, and the remainder as table sweetening additives with a small amount being exported. Artificially sweetened soft drinks in common usage to date are listed as containing cyclamate in amounts ranging roughly from 200 to 700 mg. per bottle or ten-ounce drink of a mix. Sweet mixtures with cyclamates (jams, syrups, dressings, etc.) list considerably less per serving, indeed usually below 100 mg. Prepared desserts (puddings, gelatins, cookies, pie fillings) list from 50 to 400 mg. per serving, and packed fruits 150 to 300 mg. per serving. In light of these amounts a young person, especially a teenager, might consume from 1 to 3 gm. daily in soft drinks, and an obese person following a planned reducing diet might consume from 100 to 500 mg. per day. It is not known at present what intake level of cyclamate can be generally regarded as safe. In 1968 the National Academy of Sciences and National Research Council stated that a maximum daily intake of 70 mg. per kg. of body weight, or 5.0 gm. in an adult, could be judged safe. Later the Food and Drug Administration

Present state of knowledge concerning effects of the sulfonylurea compounds in diabetes mellitus; report of the Committee on Summarization of the Conference.

1. Peripheral Tissues. No convincing evidence has been adduced that the sulfonylurea compounds increase utilization of glucose by peripheral tissues: They do not lower the blood sugar of eviscerated dogs (Levine), rabbits (Wick) or rats (Ingle) with or without supplementary insulin; they do not increase glucose uptake or glycogen deposition by isolated rat diaphragm, or glucose uptake by rat adipose tissue, in a medium of physiologic salt solution (Krebs-Ringer) where insulin has a pronounced effect (Krahl, Cahill, Clarke: Canad. M.A.J., 1956, and Field); and they do not increase the arteriovenous blood sugar difference after glucose loading (Goldner, Volk and co-workers). 2. Liver. Studies of the effects of these substances on liver glycogen levels have given conflicting results, possibly because of differences in experimental conditions such as lack of uniformity in species, nutritional state, timing of samples, and duration and intensity of treatment. There is evidence that the sulfonylurea compounds inhibit the output of glucose from the intact liver (Anderson, Bondy), especially that derived from fructose and galactose (Renold, Craig) and possibly that resulting from stimulation by glucagon and epinephrine (Izzo; not confirmed by Fajans, Anderson, Goldner). On the other hand, in in vitro experiments with liver slices from normal fasted and fed rats, addition of these compounds to the medium did not affect glycogenolysis or glucose output (Cahill, Sutherland). The ordinarily glycogenolytic effect of glucagon and epinephrine in such slices appears to be inhibited by the drugs (Vaughan). Chronic medication of normal rats was followed by a reduction in glucose-6-phosphatase of the liver (Cahill, Haist, Kuether), but this effect was in no instance correlated temporally with the hypoglycemia. It was not observed in the livers of alloxan diabetic rats. Destruction of insulin in either the whole animal or isolated liver preparations was not significantly reduced by concentrations of the drugs sufficient to cause hypoglycemia (Vaughan, Williams).

Retarded and Prolonged Action of Insulin Precipitated by Safranin

Summary It has lieen shown that the addition of a weakly alkaline, buffered solution of safranin to a solution of commercial insulin yields an insulin-containing precipitate which, when injected in suspension into animals, causes hypoglycemia of gradual onset and extended duration. The blood sugar curve so produced is similar to, but not quite so depressed as, that given by the injection of an equal amount of protamine insulin suspension. The redissolved precipitates of safranin and protamine insulin are considerably inferior to the suspensions in retarding the fall of the blood sugar and/or prolonging the period of hypoglycemia.