Chemical Diabetes Research Articles

PRINCIPLES OF ORAL CONTRACEPTION: 2. SIDE EFFECTS OF ORAL CONTRACEPTIVES

61 references are cited in a comprehensive review of the side effects of oral contraception. Thrombosis though relatively rare is the most serious risk. Other undesirable side effects include impairment of oral glucose tolerance chemical diabetes hyperlipidemia hypertension and post-pill infertility. Estrogenic side effects include action on liver leading to plasma protein changes menstrual migraines (with drop in estrogen levels) facilitation of water and salt retention slight breast development and deposition of fat on the buttocks leg cramps nausea depression libido loss cervical gland activity and vaginal secretions and lactation impairment. Progestogen side effects include weight gain depression irritability chronic fatigue loss of libido acne breakthrough bleeding and delay in reoccurrence of ovulation after end of regimen. Cholasma increases in frequency with progestogen with estrogen. Other metabolic changes brought about by oral agents are rise in copper level decline in zinc level increase in serum iron level and total iron-binding capacity and rise of protein-bound iodine level. Contraindications for oral agents are some cardiac diseases (especially pills with high estrogen) and cholestatic jaundice of pregnancy.

The role of growth hormone in the pathogenesis of diabetes mellitus in childhood

The behavior of growth hormone in basal conditions and after pharmacologic stimulations was investigated in diabetic children with and without ketoacidosis, in children of normal weight with chemical diabetes, and in obese children with reduced glucose tolerance. The plasma growth hormone values in obese children with reduced glucose tolerance did not differ from those observed in obese children with normal glucose tolerance. In children with chemical diabetes the plasma growth hormone values were normal; in newly diagnosed diabetic children without ketoacidosis the growth hormone values were usually normal during basal conditions, but in some instances they were definitely increased in spite of high blood sugar levels. In diabetic children with severe ketoacidosis there was usually a significant increase of growth hormone values notwithstanding the marked hyperglycemia.

Hormonal and metabolic disturbances during acute and subacute myocardial infarction in man

To investigate the cause of glucose intolerance (GIT), frequently seen during acute myocardial infarction (AMI), seventeen males without history of diabetes were studied with intravenous glucose tolerance tests within seventy-two hours after uncomplicated myocardial infarction and again three weeks later. Seventy percent (12/17) of the patients showed GIT during AMI. In 7 of these patients (41%) glucose tolerance (GT) remained abnormal after 3 weeks. In addition, all 7 showed markedly diminished insulin responses to glucose during both the acute and subacute phase. Therefore, their GIT was considered to be due to newly-recognized chemical diabetes. In the remaining patients in whom the initially depressed GT improved during SMI elevated serum levels of FF A, insulin, HGH and cortisol suggested the temporary presence of insulin antagonism. Increased adrenal medullary activity was not found to be a major factor inhibiting glucose tolerance.

The insulin response to glucose in patients with non-diabetic glycosuria.

Summary Glucose tolerance tests (GTT) were performed and plasma insulin levels measured by immunoassay in eighty-nine subjects previously found to have non-diabetic glycosuria (fifty-six with renal glycosuria and thirty-three with lag curves). The time-interval between the two tests varied from 6 months to 13 years. Ten patients had developed chemical diabetes but only three had symptoms. Two had initially renal glycosuria and eight lag curves. This significantly different incidence may have been due to an excess of older patients in the lag-curve group. The mean insulin response was higher in those with diabetes than in those in whom the second test was normal. The individual insulin responses were abnormal by our criteria in twenty-six subjects including six of the ten diabetics. In twenty-four subjects plasma insulin levels had been measured during the initial GTT. The insulin response had been abnormal in thirteen of these, four of whom were diabetic at follow up. In contrast only one of the eleven subjects with an initially normal insulin response had developed diabetes. It is suggested that an abnormal insulin response to glucose may be an indication of potential diabetes.

Hormonal and metabolic disturbances during acute and subacute myocardial infarction in man.

To investigate the cause of glucose intolerance (GIT), frequently seen during acute myocardial infarction (AMI), seventeen males without history of diabetes were studied with intravenous glucose tolerance tests within seventy-two hours after uncomplicated myocardial infarction and again three weeks later. Seventy percent (12/17) of the patients showed GIT during AMI. In 7 of these patients (41%) glucose tolerance (GT) remained abnormal after 3 weeks. In addition, all 7 showed markedly diminished insulin responses to glucose during both the acute and subacute phase. Therefore, their GIT was considered to be due to newly-recognized chemical diabetes. In the remaining patients in whom the initially depressed GT improved during SMI elevated serum levels of FF A, insulin, HGH and cortisol suggested the temporary presence of insulin antagonism. Increased adrenal medullary activity was not found to be a major factor inhibiting glucose tolerance.

Is there a delay in the plasma insulin response of patients with chemical diabetes mellitus?

We have compared the plasma glucose and immunoreactive insulin responses to oral glucose, intravenous glucose and intravenous tolbutamide of twenty normal subjects with those of eleven patients with chemical diabetes. The two groups were similar in terms of age, sex and degree of adiposity. The insulin response of patients with chemical diabetes was greater at every time interval during all these tests. Thus, we could document no defect in the rapidity of insulin response to these stimuli in patients with chemical diabetes. These results do not support the view that the commonest metabolic abnormality in patients with diabetes is a delay in the insulin response.

Plasma insulin in reactive hypoglycemia.

Among 663 standard four-hour oral glucose tolerance tests (OGTT) performed in a Department of Internal Medicine, forty-seven curves demonstrated reactive hypoglycemia of 45 mg. per 100 ml. or less at one or more occasions. Subsequent analysis of the records of the corresponding patients allows their partition into the following groups: IA. Obesity (11), IB. Obesity with chemical diabetes (9), II. Postgastrectomy syndrome (3), III. Chemical diabetes without obesity (1), IV. Renal glycosuria (7), V. Isolated reactive hypoglycemia (16). In order to determine the role of plasma insulin in the pathogenesis of the syndrome, the insulin response of each group of subjects presenting reactive hypoglycemia was compared to that of a control group of similar age, sex and weight with similar pathological findings but without reactive hypoglycemia. The results indicate that plasma insulin values can not account for the reactive hypoglycemia in the groups IA, IB, III and IV, and thus other factors may be responsible for the occurrence of hypoglycemia in most cases of this syndrome. In contrast, an exaggerated insulin response exists in group II, and in seven out of the sixteen cases of isolated reactive hypoglycemia. No correlation was found between the presence of clinical symptoms evoking reactive hypoglycemia during the usual life and the severity of the hypoglycemia recorded during the OGTT.

Metabolic disturbance of KK mice in overt diabetes.

KK mice, which proved to be of chemical diabetes when kept on usual laboratory chow, developed hyperglycemia with hypertrophy of epididymal adipose tissue when fed a semisynthetic diet. Effects of the semisynthetic diet on metabolic activities were investigated in vitro. In adipose tissue, lipogenesis from acetate was markedly activated, but either oxidation of glucose or lipogenesis from glucose was hardly activated. Insulin sensitivity of the tissue was diminished in glucose oxidation, but not in lipogenesis from acetate. Hepatic lipogenesis from both glucose and acetate was markedly stimulated. Thus, activation of hepatic and extrahepatic lipogenesis, and reduction of insulin sensitivity in peripheral glucose metabolism may result in the onset of overt diabetes associated with adiposity.These metabolic profiles were similar to those of genetically obese KK mice, yellow KK. A possible mechanism of the diabetogenic action of the diet is discussed on the basis of the metabolic defects of KK strain.

Glucose tolerance testing after intravenous betamethasone phosphate, with concomitant uric acid and cholesterol analyses. A reassessment of both glucocorticoid and afternoon testing in "early chemical diabetes"

The intense, sustained and predictable glucocorticoid action of i.v. betamethasone disodium phosphate (BSP) has been used as an effective method of stressing the insulinogenic reserve before glucose tolerance testing (GTT). The 13 selected patients in this study received 4.5 mg of BSP 16 to 18 hrs before ingesting a 100 g glucose load. «Early chemical diabetes» was suspected in 8 patients on the basis of the following: 1) clinical features such as hypercholesterolemia, transient glucosuria, diabetic-like peripheral neuropathies, gout, and large babies; 2) a family history of diabetes, especially when bilateral; and 3) nondiabetic or equivocal responsesboth by conventional morning glucose tolerance testing (MGTT) and afternoon glucose tolerance testing (AGTT).Every patient showed an unequivocal diabetic response after BSP priming. Five patients evidencing decreased glucose tolerance by AGTT, but not by MGTT, also were studied. Their diabetic diathesis was readily confirmed by BSP-GTT, even after improvement of glucose tolerance had been evidenced by repeat AGTT following treatment with diet and oral hypoglycemic drugs. The diagnostic and prognostic usefulness of corticosteroid-GTT remains limited, since it imposes apharmacologic stress upon the insulinogenic reserve. This contrasts with thephysiologic method of AGTT, which has demonstrated decreased tolerance in most diabetic suspects whose responses to MGTT proved nondiabetic or equivocal. Prognostically, depletion of the insulinogenic reserve is probably more advanced in the patient with «early chemical diabetes» whose diagnostic hyperglycemia is demonstrable by AGTT than when it can be evoked only after glucocorticoid priming. The paradoxic postglucose rise in the uric acid concentration, cholesterol concentration, or both, during AGTT and BSP-GTT in certain patients has been demonstrated. The implications of these phenomena relative to the pathogenesis and treatment of gout, hypercholesterolemia, and «secondary sulfonylurea failure» are discussed.

Comparison of the 50 and 100 Gram Oral Glucose Tolerance Test

A series of two 100 gm. and two 50 gm. oral glucose tolerance tests were performed on each of ninety-six young, healthy, prison inmates under rigidly controlled experimental conditions. Mean blood glucose levels for fasting, one, two, and three hour-postchallenge determinations were compared between challenges. The interrelationships of these determinations were also compared between the two standard loading doses. Mean two-hour levels were 14 to 27 per cent higher after the larger challenge. With an appropriate conversion factor, the absolute difference in two-hour values could be equated. Thus, despite these unequal means, the diagnostic information obtained with either challenge at one and two hours does not differ. The fact that the one-hour determination was not related to loading dose size or obesity as expressed by the weight index [100 (weight)/height2] and was highly correlated with the Tolerance Index, suggests that it is the preferable screening test for diabetes. Studies in other populations are needed to confirm this, however. Although mean levels at three hours were the same, the distribution of tolerance responses for this determination differed for the two challenges. An excess of both relative hypoglycemic andhyperglycemic responses occurred with the larger loading dose. These contrasting distributions suggest that the 100 gm., three-hour determination may possess unique diagnostic power to ascertainearly chemical diabetes. Until adequate criteria of an abnormal three-hour response are established, however, this determination cannot be used as a screening test for diabetes. Physiologic variability for all specific determinations and the complete tolerance test were similar for both challenges. The fact that only a moderate degree of correlation was found between repeat tolerance responses greatly compromises the clinical values of a single glucose tolerance test.

Generalized granuloma annulare: relationship to diabetes mellitus as revealed in 8 cases.

Summary Clinical or chemical (latent) diabetes was discovered in 7 of 8 patients with generalized granuloma annulare; all were women. The average age of onset of their disease was 50 years. Treatment with chlorpropamide and low carbohydrate diet seemed to alleviate the skin manifestations in 6 of 7 patients so treated.

Microcirculation in young adults with cystic fibrosis: Retinal and conjunctival vascular changes in relation to diabetes

Conjunctival biomicroscopy and retinal photography were utilized in 67 patients with cystic fibrosis, ages 15 to 26 years, to detect a possible prediabetic vascular change. Examination revealed venular congestion and tortuosity as well as venular and arteriolar red cell aggregation. These changes were related to the severity of the cystic fibrosis and not to glucose intolerance. Both clinical and chemical diabetes occur more frequently in older patients with cystic fibrosis than in normal subjects. The diabetes is not related to the severity of the cystic fibrosis. A prediabetic vascular change could not be reliably detected by this study.

Clinical and Chemical Diabetes in Offspring of Diabetic Couples

Clinical and Chemical Diabetes in Offspring of Diabetic Couples

Insulin responses of children with chemical diabetes mellitus.

Abstract: Diminished insulin response to hyperglycemia has been thought to be the genetically determined prerequisite for the development of diabetes mellitus, best demonstrated in the insulin-deficient child with overt disease. Of eight children, with chemical diabetes mellitus, three and a half to 16 years of age, four had normal or increased plasma immunoreactive insulin responses to oral glucose loading on analysis for insulin-glucose ratios (microunits of insulin per milliliter over glucose, milligrams per 100 ml). In three of these patients the apparent insulin hypoactivity was ameliorated by tolbutamide, which diminished the insulinemia while either correcting or not markedly altering the glucose response. Thus, there appears to be a stage of essential diabetes mellitus in childhood that is characterized by a reduced effectiveness of circulating immunoreactive insulin. Tolbutamide may improve the glucose-insulin relation in certain patients and might prevent or delay progression to diabetes mellitus.

SIMPLIFYING THE CLINICAL PROBLEM OF GLYCOSURIA IN PREGNANCY

The complex problem of glycosuria in pregnancy has been tackled by defining a subgroup with glycosuria to testing with the glucose-oxidase test strip 'Clinistix' in a second fasting morning urine specimen. This group has been compared with a " random glycosuria group " composed of women with postprandial but not fasting glycosuria to clinistix. A significant correlation was found between second fasting morning glycosuria and chemical diabetes, but there was no such correlation with random glycosuria. The finding of " random glycosuria " did not contribute to the incidence of chemical diabetes in women with obesity or a family history of diabetes in the first degree relatives. On the other hand second fasting morning glycosuria was associated with an increased incidence of chemical diabetes in these categories of women. The possible importance of these findings is that many fewer women with glycosuria in pregnancy need to be tested for diabetes since it appears that it is only the second fasting morning glycosuric group (8 per 1000 antenatal women) that is significantly at risk.

FACTORS AFFECTING SENSITIVITY OF GLUCOSE-OXIDASE STRIPS USED TO TEST FOR GLYCOSURIA

The glucose-oxidase test-strip (' Clinis-tix ') has been shown not to react with the low concentration of glucose occurring normally in the second fasting urine specimen of pregnant women with normal intravenous glucose tolerance, but in women with a positive reaction there is a significant correlation with gestational chemical diabetes. The sensitivity of clinistix is consistent within one bottle but less so between different bottles even of the same batch. Age and exposure to air reduce sensitivity. pH and temperature are unimportant factors. False-negative results are likely to be due to ascorbic acid in concentrations found in pregnancy urine, although this would seldom have affected the issue when assessing potential diabetes on the single criterion of second fasting morning glycosuria. Uric acid did not give a false-negative reaction. False-positive results could result from contamination of the glassware by glucose, from oxidising agents, or from the action of catalase present in pus; in practice, pus does not seem to be important.

CLINICAL AND CHEMICAL DIABETES IN OFFSPRING OF DIABETIC COUPLES

Abstract A total of 678 glucose tolerance tests (oral glucose, cortisone-primed oral glucose, intravenous glucose and intravenous tolbutamide tests) were performed upon 155 of 274 offspring from 80 conjugal diabetic parents. The diabetic status of the untested offspring was determined by communication with parent or sibling. Administration of multiple tests (of various types) or repeated oral glucose tolerance tests detected a higher frequency of chemical diabetes than that obtained after a single test. The overall frequency of chemical diabetes (41 to 62 per cent, depending on the age and weight of the offspring) was considerably higher than that of overt diabetes (8.8 per cent). The oral glucose tolerance test appeared to be as sensitive as any other glucose tolerance test in detecting chemical diabetes. In such persons, many of whom were nonobese teen-agers and young adults, abnormal tests were frequently followed by one or more normal tests, as were normal tests followed by abnormal tests in no predic...

Diabetogenic action of streptozotocin: relationship of dose to metabolic response

The relationship between the dose of intravenously administered streptozotocin (a N-nitroso derivative of glucosamine) and the diabetogenic response has been explored by use of the following indices of diabetogenic action: serum glucose, urine volume, and glycosuria, ketonuria, serum immunoreactive insulin (IRI), and pancreatic IRI content. Diabetogenic activity could be demonstrated between the doses of 25 and 100 mg/kg, all indices used showing some degree of correlation with the dose administered. Ketonuria was only seen with the largest dose, 100 mg/kg. The most striking and precise correlation was that between the dose and the pancreatic IRI content 24 hr after administration of the drug, and it is suggested that this represents a convenient test system either for both related and unrelated beta cytotoxic compounds or for screening for modifying agents or antidiabetic substances of a novel type. Ability to produce graded depletion of pancreatic IRI storage capacity led to an analysis of the relationship between pancreatic IRI content and deranged carbohydrate metabolism. Abnormal glucose tolerance and insulin response were seen when pancreatic IRI was depleted by about one-third, while fasting hyperglycemia and gross glycosuria occurred when the depletion had reached two-thirds and three-quarters, respectively. The mild yet persistent anomaly produced by the lowest effective streptozotocin dose, 25 mg/kg, exhibits characteristics resembling the state of chemical diabetes in humans and might thus warrant further study as a possible model. Finally, the loss of the diabetogenic action of streptozotocin by pretreatment with nicotinamide was confirmed and was shown to be a function of the relative doses of nicotinamide and streptozotocin and of the interval between injections.

Chemical and early overt diabetes mellitus in children. I. Effect of glucagon on "insulin reserve".

Glucose disappearance rates and serum immunoreactive insulin levels following the infusion of glucose and glucose with glucagon were studied in eleven normal subjects, fortyeight children classified as chemical diabetics, and seventeen children with the recent onset of overt diabetes in the early recovery phase of the disease. Children with chemical diabetes had significantly lower glucose disappearance rates than the normal controls and significantly higher disappearance rates than the children with overt diabetes. Compared with the normal controls, the change in glucose disappearance rates due to glucagon was significantly reduced in chemical diabetics and absent in overt diabetics. Normal subjects and chemical diabetics responded to glucose and glucagon infusion by increasing the serum IRI levels. Chemical diabetics formed a heterogeneous group with respect to the serum IRI response to glucagon. Children classified as “late” chemical diabetics, like the overt diabetics, had decreased serum IRI responses to glucagon. Children with chemical diabetes who have blood sugar values outside the ninety-seventh and third percentiles of the distribution of normal values during an oral glucose tolerance test are already in an advanced (late) stage of chemical diabetes and are likely to have their disease progress rapidly to overt diabetes. Children with “late” chemical diabetes have glucose disappearance rates less than 1.1 per cent per minute, less than +0.3 change in glucose disappearance rates after glucagon stimulation and an impaired serum IRI response to an intravenous infusion of glucose or glucose and glucagon. Identification of children in earlier stages of chemical diabetes is desirable in order to evaluate the feasibility of altering the progressive loss of insulin reserve.

Chemical and early overt diabetes mellitus in children. II. Effect of intravenous tolbutamide on "insulin reserve".

Blood sugar and serum immunoreactive insulin (IRI) response to a rapid intravenous infusion of tolbutamide was studied in twelve normal subjects, forty-four children with chemical diabetes and ten children with overt diabetes mellitus of recent onset. The diagnosis of chemical diabetes was based on two or more abnormal oral glucose tolerance tests, separated by at least two months' time interval. Of the forty-four children with chemical diabetes, twenty-four children had one or more blood sugar values outside the ninety-seventh or third percentile during oral glucose tolerance tests (“late” chemical diabetes) and had impaired tolbutamide responses at thirty minutes which were significantly different from normal controls and from the children with overt diabetes. Serum IRI levels were similar in chemical diabetics and normal subjects. Overt diabetics had decreased IRI responses to tolbutamide. The tolbutamide test as performed will not detect children in the earlier stages of chemical diabetes. Until a more sensitive and reliable test is devised, it is necessary to rely on repeated oral glucose tolerance tests to identify children in the earlier stages of chemical diabetes. Longitudinal studies of a large group of children with chemical diabetes are necessary in order to extend our knowledge of the pathophysiology of the disorder and to establish more specific and reliable criteria to define the stages of the disease.