Showing papers in "Diabetes in 1978"
TL;DR: Slow motion photography revealed that diabetic erythrocytes restore their shape less rapidly than nondiabetic ery throatcytes, indicating that their reduced deformability is due to an elevation of either intraeriesthrocyte or membrane viscosity rather than to increased resistance to bending.
Abstract: The flow properties of individual erythrocytes have been studied in glass micropipets 4 μ internal diameter. The pressure gradient required to establish a standard oscillatory movement over a 130-μ path in a three-second time period was measured in paired studies comparing diabetic and control erythrocytes suspended in Ringer solution. The pressure requirement was regularly elevated for the diabetic erythrocytes, averaging 50 per cent greater than the controls. Studies of erythrocytes comparing alloxan-diabetic rats with control rats demonstrated a similar elevation in required pressure. Red cells from subjects with hereditary spherocytosis offered less flow resistance than diabetic cells, and red cells from rheumatoid arthritics required no pressure increment. When erythrocytes are ejected from a 4-μ micropipet they return quickly to a discoid shape using stored elastic energy. Slow motion photography revealed that diabetic erythrocytes restore their shape less rapidly than nondiabetic erythrocytes, indicating that their reduced deformability is due to an elevation of either intraerythrocyte or membrane viscosity rather than to increased resistance to bending. Diabetes is regularly associated with an increased intracellular hemoglobin Alc; it is possible that hemoglobin Ale could raise intraerythrocyte viscosity. The observed disturbance in flow properties of individual erythrocytes is subtle. It would affect the flow of blood, particularly through active muscle, and modify the pressure exerted by individual erythrocytes on the muscle capillary wall.
369 citations
TL;DR: The readily available human erythrocyte has both specific insulin binding sites and binding characteristics similar to other human cell types, and has provided the basis for further clinical investigation of polypeptide hormone receptors on human ERYthrocytes.
Abstract: Highly specific insulin receptors have been identified on human erythrocytes. A modification of the monocyte insulin radioreceptor technique permitted distinct separation of human erythrocytes with their bound insulin from the free insulin. When incubated with 80 pg. per milliliter of 125I-insulin (pH 8.0, 3.5 hours, 15 degrees C.), erythrocytes from 17 normal volunteers specifically bound 10 per cent (+/- 1.450 S.D.) of the total 125I-insulin. Less than 15 per cent of the total 125I-insulin bound was nonspecific. Binding of 125I-insulin to human erythrocytes was dependent on pH and temperature. Less than 5 per cent of the insulin available to the plasma membrane was degraded. Both calcium and magnesium enhanced 125I-insulin binding by 100 per cent but had no synergistic effect when mixed in a 1:1 molar ratio. Scatchard analysis of the binding data resulted in a curvilinear plot with characteristics typical of negative cooperative interactions between receptor sites and with an unoccupied site affinity constant of 0.1 X 10(8) M-1. Human erythrocytes have 2,000 insulin binding sites per erythrocyte with 14 sites per square micrometer of surface area. The readily available human erythrocyte, thus, has both specific insulin binding sites and binding characteristics similar to other human cell types. These studies have provided the basis for further clinical investigation of polypeptide hormone receptors on human erythrocytes.
338 citations
TL;DR: Differences in C-peptide antisera are a major reason for the variation in the concentration of circulating CPR as measured in different, C- peptide immunoassays.
Abstract: The plasma C-peptide immunoreactivity (CPR) in 10 normal subjects varied considerably when measured with different antisera in parallel assays The CPR level correlated with the blank “CPR” value measured in plasma devoid of C-peptide and to a lesser degree with the sensitivity of the standard curves obtained with the individual antisera Storage of plasma samples at different temperatures and for different lengths of time before the analyses were carried out resulted In further variation in the CPR results This was caused by a time- and temperature-dependent fall in CPR, which was more pronounced with some antisera than with others This sensitivity to storage of plasma did not correlate with the antigenk characteristics of the antisera as determined by their reactivity with 11 specific fragments of the C-peptide molecule The contribution of human proinsulin to the CPR concentration in normal subjects was considered to be negligible even though the relative immunoreactivity of human proinsulin and C-peptide ranged from 11 to 143 per cent among these antisera These results suggest that differences in C-peptide antisera are a major reason for the variation in the concentration of circulating CPR as measured in different, C-peptide immunoassays
306 citations
TL;DR: Granulocyte adherence may also be impaired in poorly controlled diabetic patients and a defect of this type may compromise the normal inflammatory response in some diabetics and impair their capacity to resist infection.
Abstract: When the ability of granulocytes from 10 poorly controlled diabetic patients with fasting hyperglycemia and no evidence of ketoacidosis (mean fasting glucose 293 +/- 20 mg. per 100 ml.; mean +/- S.E.M.) to adhere to a nylon fiber column was assessed, the number of adherent granulocytes from whole blood was only 53 +/- 6 per cent of the values observed in controls. After antidiabetic treatment for one to two weeks and lowering of fasting glucose levels (mean 198 +/- 29 mg. per 100 ml.), adherence improved significantly (p less than 0.01) in the diabetics; however, their values were still subnormal (diabetic 74 per cent +/- 8 of control; p less than 0.02). Adherence values before and after treatment correlated with the fasting glucose level (r = 0.88, p less than 0.001). These findings suggest that, in addition to previously reported abnormalities in migration and the ingestion and killing of bacteria, granulocyte adherence may also be impaired in poorly controlled diabetic patients. This functional abnormality correlates directly with the fasting glucose and is reversed by insulin treatment. A defect of this type may compromise the normal inflammatory response in some diabetics and impair their capacity to resist infection.
272 citations
TL;DR: Data suggest that a primary defect exists in intracellular killing of staphylococci by granulocytes from poorly controlled diabetics in addition to that previously shown in engulfment, and this bactericidal activity becomes more efficient when the diabetes is brought under better control.
Abstract: Granulocytes of patients with diabetes mellitus have an impaired capability to engulf bacteria, but it is not clear whether subsequent intracellular killing, which has separate energy sources, is also defective. We separately assayed engulfment and intracellular killing of Staphylococcus aureus 502a by granulocytes of 17 diabetic patients with fasting hyperglycemia to better characterize the phagocytic defect. Diabetic granulocytes engulfed a smaller proportion than controls of a 10 6 inoculum of bacteria after 20 minutes of incubation in vitro (56.8 ± 9.4 per cent versus 72.4 ± 3.6 per cent, mean ± S.E. of 10 patients and paired controls, p 6 inoculum) was less (p These data suggest that a primary defect exists in intracellular killing of staphylococci by granulocytes from poorly controlled diabetics in addition to that previously shown in engulfment. This bactericidal activity becomes more efficient when the diabetes is brought under better control.
258 citations
TL;DR: The average serum lipid and lipoprotein pattern of insulin-treated chronic diabetic patients is not more atherogenic than that of nondiabetic subjects of similar age and sex, and the increase of HDL-cholesterol observed in the diabetic subjects should make them less liable to develop coronary heart disease.
Abstract: In view of the high incidence of coronary heart disease in insulin-dependent diabetes, we determined cholesterol and triglyceride concentrations in serum and in three major lipoprotein fractions of 170 nonuremic middle-aged diabetic patients who had been treated with insulin for a minimum of 10 years. In addition, postheparin plasma lipoprotein lipase activity was measured in a subsample of the diabetic subjects. The diabetics had serum cholesterol and triglyceride concentrations similar to those of nondiabetic control subjects of the same age and sex. However, the concentration of high density lipoprotein (HDL)-cholesterol was significantly higher in both male and female diabetic patients than in respective controls (P We conclude that the average serum lipid and lipoprotein pattern of insulin-treated chronic diabetic patients is not more. atherogenic than that of nondiabetic subjects of similar age and sex. On the contrary, the increase of HDL-cholesterol observed in the diabetic subjects should make them less liable to develop coronary heart disease. Thus, the excess cardiovascular disease that is associated with insulin-dependent diabetes must be accounted for by other factors.
242 citations
TL;DR: Comparison of the Hb AI (Hb AIa+b+c) determinations showed an acceptable correlation of percentages obtained by the relatively laborious macrocolumn procedure and the more facile microcolumn procedure, indicating that the latter would be clinically useful.
Abstract: Fifty-seven children who attended a diabetes camp were divided into five groups on the basis of retrospective evaluation of the management of their diabetes mellitus over the previous three or more months. Shortly after their arrival at camp, fasting blood samples were obtained for the measurement of glucose and the quantitation of Hb A I and for hemoglobin typing. Samples were obtained from 12 normal (nondiabetic) camp personnel at the same time. The Hb A I components were measured by the “macrocolumn” procedure of Trivelli et al., by the colorimetric procedure of Flukinger and Winterhalter, and by a new microcolumn procedure employing columns and reagents provided by Isolab, Inc. As might be expected from a number of previous reports by other investigators, there was no significant correlation of the percentage of Hb A I with single fasting blood sugar values. Hb A I tended to decrease as the management of diabetes became more adequate according to clinical ratings. Comparison of the Hb A I (Hb A Ia+b+c ) determinations showed an acceptable correlation of percentages obtained by the relatively laborious macrocolumn procedure and the more facile microcolumn procedure, indicating that the latter would be clinically useful. Values of Hb A Ic obtained by the colorimetric procedure, which has been proposed as a procedure suitable for the clinical laboratory, did not correlate well with Hb A Ic values determined by the macrocolumn technique, nor did these show as good an inverse relationship to the ratings of the management of diabetes.
224 citations
TL;DR: Assessment of heart rate variability by reference to standard deviation of R-R intervals is unhelpful; a single deep breath is a more potent stimulus for heart rate change than repeated deep breaths in diabetic subjects; and measurement of this response together with the bradycardia evoked by the Valsalva maneuver obviate the need to perform invasive investigations.
Abstract: A comparison of the cardiac responses to a variety of maneuvers that modify cardiac vagal tone was made in nondiabetic and diabetic subjects. We concluded that assessment of heart rate variability by reference to standard deviation of R-R intervals is unhelpful; that a single deep breath is a more potent stimulus for heart rate change than repeated deep breaths in diabetic subjects; and that measurement of this response together with the bradycardia evoked by the Valsalva maneuver obviate the need to perform invasive investigations, such as the estimation of baroreflex sensitivity, or tedious procedures, such as apneic face immersion. In a small number of subjects, heart responses to lower body, negative pressure provided information not forthcoming from other tests.
218 citations
TL;DR: The present study is based upon an examination of sympathetic chains obtained at autopsy in patients dying at the Massachusetts General Hospital, who all had a well-documented history of diabetes mellitus or chronic alcoholism and some of them had a complicating polyneuropathy.
Abstract: (All are verbatim summaries) Smith, B. (Dept. of Pathol., St. Bartholomew's Hosp., London, England): NEUROPATHOLOGY OF THE OESOPHAGUS IN DIABETES MELLITUS. J. Neurol. Neurosurg. Psychiatry 37:1151-54, 1974. Abnormalities of the innervation of the oesophagus have been shown in 18 out of 20 unselected diabetics without clinical dysphagia or neuropathy. The changes appear to be in the axons of the extrinsic and intrinsic parasympathetic fibres. It is probable that, as in the peripheral nerves, the major changes are in the Schwann cells, although here the affected fibres are unmyelinated. Appenzeller, 0.; and Richardson, E. P., Jr. (Depts. of Pathol. and Neurol.-Neuropathol., Harvard Med. Sch., and the Charles S. Kubik Lab. for Neuropathol. of the James Homer Wright Pathol. Lab., Mass. Gen. Hosp., Boston): THE SYMPATHETIC CHAIN IN PATIENTS WITH DIABETIC AND ALCOHOLIC POLYNEUROPATHY. Neurology 16:1205-09, 1966. Autonomic function may be defective in patients with diabetic and alcoholic neuropathy. Thus, reflex circulatory adjustments which occur after sudden changes in posture and depend on sympathetically mediated vasoconstriction are impaired in some patients with these disorders. Thus far, however, no systematic investigation has been undertaken in an attempt to correlate these functional deficits with the morphological appearance of the autonomic ganglia or nerves. The present study is based upon an examination of sympathetic chains obtained at autopsy in patients dying at the Massachusetts General Hospital. They all had a well-documented history of diabetes mellitus or chronic alcoholism, and some of them had a complicating polyneuropathy. 1054 DIABETES, VOL. 27, NO. 10
215 citations
TL;DR: The cytologic composition of the pancreatic islets of 58 insulin-dependent diabetics with age of onset of the disease before the age of 40 and a duration of from a few days to 37 years was studied with the aid of Sternberger's immunocytochemical method, and it was revealed that these cells are not inactive but are actively secreting glucagon or somatostatin.
Abstract: The cytologic composition of the pancreatic islets of 58 insulin-dependent diabetics with age of onset of the disease before the age of 40 and a duration of from a few days to 37 years was studied with the aid of Sternberger9s immunocytochemical method. Four types of islet cells were stained with specific antisera: β cells (insulin), α cells (glucagon), D cells (somatostatin), and PP cells (pancreatic polypeptide). β cells were found in 14 of 16 recent-onset cases, in seven of 14 patients having diabetes for less than 11 years, and in five of 28 patients in whom the disease had been present for a longer time. In all these cases, the number of β cells was well below normal. They showed cytologic features of functional hyperactivity. The majority of the islets, even in recent-onset cases, were devoid of β cells and were composed of thin cords of islet cells. Immunocytochemical staining revealed that, contrary to the classic opinion, these cells are not inactive but are actively secreting glucagon or somatostatin. In many long-term juvenile diabetics, the glucagon-containing α cells appeared very numerous, but it remains to be ascertained whether this represents an apparant or a true hyperplasia. Insulitis was found in 11 of the 16 recent-onset cases. In one case, the lymphocytic infiltration was found only in islets containing β cells but was strikingly absent in the islets composed of glucagon-, somatostatin-, and PP-cells. Images of islet regeneration, with neoformation of β cells and other islet-cell types from centroacinar and ductular cells could still be detected focally in a few recent-onset cases. With a disease of longer duration, an atypical type of islet regeneration, originating in the epithelium of small- and medium-sized ducts, becomes more prevalent and produces islets solely composed of PP cells.
206 citations
TL;DR: Results imply that alterations in nephron hemodynamics combine with the diabetic state to influence the rate of development of diabetic glomerulopathy in rats.
Abstract: Rats with classic Goldblatt (two-kidney) hypertension had diabetes induced by streptozotocin. After four months of diabetes, glomeruli of the unclipped kidney of hypertensive diabetic rats had markedly increased diabetic changes, including mesangial matrix thickening and mesangial immunoglobulin (IgG and IgM) and complement (C3) localization, when compared with glomeruli of the contralateral-clipped kidneys. Further, glomeruli of the unclipped kidneys of hypertensive diabetic animals had more mesangial thickening and IgG and IgM staining than glomeruli of normotensive diabetic rats. Although glomeruli of clipped kidneys in hypertensive diabetic rats had less mesangial thickening than glomeruli of normotensive diabetic rats, this did not reach statistical significance. However, these glomeruli did have significantly less IgG, IgM, and C3 staining compared with glomeruli of normotensive diabetic animals. Mesangial thickness in glomeruli of clipped and unclipped nondiabetic hypertensive rats did not differ from that in normal animals. However, there was less mesangial IgG staining in clipped than in unclipped kidneys of nondiabetic hypertensive rats or in kidneys of normal animals. We have interpreted these results to imply that alterations in nephron hemodynamics combine with the diabetic state to influence the rate of development of diabetic glomerulopathy in rats.
TL;DR: Diabetic rats with unilateral nephrectomy increases, at as early as three months, the severity of diabetic glomerular lesions, and Nephrectomy had no detectable effects onglomerular morphology or im-munohistochemistry of nondiabetic rats.
Abstract: One month following induction of diabetes with streptozotocin, one half of diabetic and control rats underwent unilateral nephrectomy. Subsequently, all animals were studied with respect to renal function and glomerular alterations of diabetes. Blood pressure levels were similar in all animals. Diabetic and control animals with unilateral nephrectomy had similar but elevated serum creatinine levels and lower creatinine clearance values as compared with the intact rats. However, on a per kidney basis the creatinine clearance levels were higher in the animals with unilateral nephrectomy. At both three and six months following nephrectomy, markedly increased mesangial matrix thickening and mesangial deposition of IgG and C3 were observed in diabetic rats with unilateral nephrectomy as compared with intact diabetic animals. Nephrectomy had no detectable effects on glomerular morphology or immunohistochemistry of nondiabetic rats. Thus, unilateral nephrectomy in the rat increases, at as early as three months, the severity of diabetic glomerular lesions.
TL;DR: A sample-preparation technique using filtration was developed that shortened and simplified preparation of venous blood and allowed use of capillary samples, and can facilitate large-scale clinical investigations and permit biochemical investigations of the metabolism and formation of hemoglobin A1c.
Abstract: Hemoglobin A1c (HbA1c) is a glycosylated derivative of hemoglobin and is one of a family of derivatives whose concentrations are elevated in patients with diabetes mellitus. Published methods for the measurement of HbA1c are relatively tedious and require modest amounts of blood. A high-performance liquid chromatographic (HPLC) method for the determination of HbA1c is presented. The method is rapid (20 minutes), precise (coefficient of variation of 5-10 per cent), uses small amounts of sample (3 microliter.), can be automated. A sample preparation technique using filtration was developed that shortened and simplified preparation of venous blood and allowed use of capillary samples. HbA1c was measured by this method in three age-stratified groups of controls and a group of insulin-requiring juvenile diabetics. There was clear separation of HbA1c values between all normals (5.9 +/- 1.3, 5.6 +/- 0.7, 7.1 +/- 0.9 per cent) and the diabetics (12.1 +/- 2.4 per cent). Use of this method can facilitate large-scale clinical investigations and permit biochemical investigations of the metabolism and formation of hemoglobin A1c where small sample sizes are necessary.
TL;DR: Evidence is provided for monogenic control of tolbutamide metabolism in man and the results suggest that fixed dosage regimens of this drug, as were prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.
Abstract: This study was designed to focus on the genetic control of tolbutamide dispositon in humans and to provide insight into the potential for high accrued blood levels in individuals receiving fixed dosage regimens. Tolbutamide was administered intravenously to 42 nondiabetic subjects, eight of their relatives, and to five sets of twins. A ninefold variation in the rate of tolbutamide disappearance from plasms (Kd) was found. This variation was characterized by a trimodal frequency distribution, suggestive of monogenic inheritance and consistent with pedigree analysis, indicating autosomal transmission of rapid and slow inactivation of tolbutamide. A heritability value of 0.995 for Kd indicated little influence of environmental factors on variation of this rate. Interindividual differences in the binding of 35S-tolbutamide to serum proteins were also assessed. No correlation was found between tolbutamide serum protein binding affinity and Kd. Analysis of the metabolites of tolbutamide in urine samples provided evidence for the microsomal oxidation of the drug to hydroxytolbutamide as the primary site of genetic control. In conclusion, this study provides evidence for monogenic control of tolbutamide metabolism in man. The results suggest that fixed dosage regimens of this drug, as were prescribed in the controversial University Group Diabetes Program study, might lead to higher accrued blood levels in slow inactivators.
TL;DR: The performance of the system parallels that of the normal pancreas and lends support to the hypothesis that biphasic insulin responses to glucose challenges are essential for the economy of insulin and the precision of regulation seen in healthy subjects.
Abstract: (All are verbatim summaries) Albisser, A. M., Leibel, B. S., Ewart, T. G., Davidovac, Z., Botz, C. K., and Zingg, W. (Dept. of Med. Eng. and Surg. Res., Hosp. for Sick Children, Banting and Best Dept. DIABETES, VOL. 28, NO. 1 81 CLOSED-LOOP AND OPEN-LOOP DEVICES FOR BLOOD GLUCOSE CONTROL of Med. Res., and Inst. of Med. Sci., Univ. of Toronto, and Dept. of Rehab. Med., Wellesley Hosp., Toronto, Canada): An Artificial Endocrine Pancreas. Diabetes23:389,1974. In order to regulate the blood sugar in the intact depancreatized dog as precisely as that accomplished by its normal pancreas, specific equipment has been devised to deliver insulin or glucose continuously and establish normoglycemia both in the fasting and glucose-loaded states. A minicomputer was programmed to respond to the constantly monitored whole blood glucose by injecting appropriate insulin or glucose intravenously to maintain or restore the normal blood sugar. Standardized glucose challenges consisting of uniform infusions of 10 mg. glucose per kg. min. for sixty minutes were applied to assess the performance of the artificial pancreas. Direct control which relates insulin dosage to the level of the circulating blood sugar results in a response to the challenge resembling mild maturity-onset diabetes both in the abnormally high blood sugar response to glucose loading and in the large amount of insulin required to effect a return to normoglycemia. In contrast, control based on projected (predicted) values of blood sugar not only prevents the abnormal rise but consumes in some cases only 10 per cent of the insulin used for the same glucose load. The performance of the system parallels that of the normal pancreas and lends support to the hypothesis that biphasic insulin responses to glucose challenges are essential for the economy of insulin and the precision of regulation seen in healthy subjects. Pfeiffer, E. F., Thum, Ch., and Clemens, A. H. (Dept. of Endocrinol. and Metab., Centr. of Intern. Med. and Pediatr., Univ. of Ulm, Germany, and Life Science Instruments, Miles Lab , Elkhart, Ind.): The Artificial Beta Cell—A Continuous Control of Blood Sugar by External Regulation of Insulin Infusion (Glucose Controlled Insulin Infusion System). Horm. Metab. Res. 6:339,1974.\" Continuous control of blood sugar in diabetics without dietary restriction has been effected by a Glucose Controlled Insulin Infusion System (GCIIS) consisting of an automatic blood glucose determination apparatus, a dedicated microcomputer, allowing the optimal adaptation of the diabetic to the artificial endocrine pancreas, a special insulin pump and an automatic printer. Insulin-dependent juvenile diabetics and diabetic subjects suffering from diabetic coma and ketoacidosis were successfully controlled and corrected for various periods of time, exhibiting completely normal blood glucose values despite unrestricted food intake. Future developments are seen on the one hand in the further improvement of the present apparatus for complete automatic treatment of acute diabetic conditions, e.g. diabetic coma, preand post-operative care of the diabetic subject, including correction of electrolyte and other disturbances. On the other hand, a smaller portable instrument should permit the diabetic subject temporarily after food intake to maintain completely normal blood glucose concentrations, preventing the presently unavoidable excessive blood glucose fluctuations. Kraegen, E. W., Campbell, L. V., Chia, Y. 0., Meier, H., and Lazarus, L. (Garvan Inst. of Med. Res., St. Vincent's Hosp., Sydney, Australia): Control of Blood Glucose in Diabetics Using an Artificial Pancreas. Aust. N. Z. J. Med. 7:280, 1977. Studies have been performed using an on-line computer system programmed for blood glucose control of insulin and dextrose infusion (artificial pancreas). The aim of these studies was to test performance of the artificial pancreas and to suggest directions for future optimisation. Blood glucose stabilisation studies of diabetic volunteers were extended throughout the day and included three main meals and light exercise periods. Monitoring of blood glucose profiles of the same diabetics after depot insulin were performed on a separate occasion for comparison. The presence of insulin antibodies did not impair operation of the artificial pancreas. Most of the insulin infused by the artificial pancreas was to initially correct hyperglycaemia with relatively little required to subsequently maintain euglycaemia. The afternoon intra-meal average infusion rate was 0.9 U/hr. It is suggested that correction of fasting hyperglycaemia and maintenance of euglycaemia in diabetics be treated as separate control problems for the artificial pancreas. The overall ability of the artificial pancreas to control blood glucose to a degree not attainable by conventional insulin therapy is confirmed, in this case under conditions which include patient activity. Slama, G., Hautecouverture, M., Assan, R., and Tchobroutsky, G. (Dept. of Diabetes, Univ. of Paris VI, Hotel-Dieu Hosp., Paris, France): One to Five Days of Continuous Intravenous Insulin Infusion on Seven Diabetic Patients. Diabetes 23:732, 1974.\" Regular insulin was infused from one to five days in seven adult diabetic volunteers previously treated with subcutaneous insulin three times a day. Through a catheter inserted in a peripheral vein, a small pump delivered 66 ± 10 units of insulin per day in a 131.0 ± 4.0 ml. solution at mean rates of 26 ± 4 mU./min. between meals and 373 ± 58 rnU/ min. during meals; 40 per cent of the total daily dose was given during the three meal periods. These rates were precalculated. Patients were ambulatory. Blood glucose was assayed every fifteen minutes for eight hours during the postprandial periods and hourly otherwise. The overall highest mean values were observed ninety minutes after breakfast (138 ± 17 mg./100 ml.) and four hours after dinner (121 ± 18); the lowest were 73 ± 7, 64 ± 7, 72 ± 15 at the end of the three high concentration insulin infusion periods and 56 ± 7 at 6 a.m. During insulin infusions the mean values of blood glucose parameters were as follows: 89 ± 7 mg./100 ml. for the mean blood glucose level; 66 ± 9 for the mean amplitude of glycemic excursion; and 17 ± 5 for the modified Schlichtkrull's M coefficient. Insulin infusions gave significantly lower blood glucose levels during the night and at breakfast than insulin three times a day and higher blood glucose values before lunch. Both technics gave very good control of diabetes. Insulin infusions without blood glucose monitoring are feasible for several days in ambulatory patients. Genuth, S., and Martin, P. (Saltzman Inst. for Clin. Invest, and Div. of Invest. Med., Mount Sinai Hosp. of Cleveland, and Case Western Reserve Univ. Sch. of Med., Cleveland, 82 DIABETES, VOL. 28, NO. 1 JULIO V. SANTIAGO AND ASSOCIATES Ohio): Control of Hyperglycemia in Adult Diabetics by Pulsed Insulin Delivery. Diabetes 26:571, 1977.\" Nine adult diabetic subjects were treated for two weeks by an intravenous insulin-delivery system that provided preprogramed five-hour pulses of insulin with each meal such that a normal diurnal pattern of plasma insulin was attained. Plasma insulin peaked at 800 per cent of basal and at approximately 45 minutes after the onset of each pulse. On day 14, mean plasma glucose (hourly sampling x 22) was 94 mg./100 ml., with a range of 66 to 125 mg./100 ml. Eighty-eight per cent of all values were between 50 and 150 mg./100 ml. The dose of insulin required correlated significantly with the degree of obesity. On the first posttreatment day, hourly plasma glucose remained significantly below pretreatment levels while the endogenous plasma insulin area increased 46 per cent above pretreatment values (p < 0.01). Six of the patients still exhibited slight improvement in glucose tolerance for seven days while on diet but not on insulin treatment. It is concluded that insulin replacement, coordinated with meals in a physiologic manner, can virtually normalize plasma glucose even without feedback control of delivery rates. Definite but transient remission of beta-cell dysfunction may follow. Deckert, T., and Lorup, B. (Steno Mem. Hosp., Gentofte, Denmark): Regulation of Brittle Diabetics By A Preplanned Insulin Infusion Programme. Diabetologia 12: 573, 1976. Eleven brittle diabetics, mean duration 11.5 years, all treated with highly purified porcine NPH insulin twice daily, were placed on highly purified porcine regular insulin 4 times daily for 2 days. Thereafter pre-planned intravenous insulin infusion was started. Insulin in an amount corresponding to the daily insulin requirement was infused by a mobile electric infusion pump at precalculated rates between 30 and 7 ml/hour during 2 days. The patients were ambulatory. Capillary blood glucose was taken every 30 min. after meals and every two hours during the night. After an equilibration period of 7 hours, blood glucose fluctuations were in the physiological range in nearly all patients during the infusion period. [Only 1.3% of the blood samples showed glucose levels lower than 2.5 mmol/l and 2.9% levels exceeding 10.0 mmol/l during the infusion days]. Mean blood glucose (MBG) was 6.0 ± 0.9 mmol/l (mean ± s.d.), the standard deviation of MBG was 1.8 ± 0.5 mmol/l, the mean amplitude of blood glucose excursions (MAGE) 4.7 ± 1.4 mmol/l, and glucosuria 3.1 ± 3.9 g/day. All these data of glucose homeostasis were significantly lower during the infusion days. The incidence of hypoglycaemic attacks was low (0.32/patient/day) and not significantly higher than during NPH treatment. It is concluded that near normal blood glucose fluctuations can be achieved in brittle diabetics by pre-planned insulin infusion without blood glucose monitoring. Marliss, E. B., Murray, F. T., Stokes, E. F., Zinman, B., Nakhooda, A. F., Denoga, A., Leibel, B. S., and Albisser, A. M. (Dept. of Med., Toronto Gen. Hosp., and Res. In
TL;DR: The findings imply a poor defense mechanism against fibrin deposits in the vessel walls in diabetes, which might contribute to the development of diabetic microangiopathy.
Abstract: (All are verbatim summaries) Aimer, Lars-Olof; and Pandolfi, Maurizio (Koagulationslaboratoriet and Dept. of Intern. Med., Allmanna, Malmo, Sweden): FlBRINOLYS1S AND DIABETIC RETINOPATHY. Diabetes 25 (Suppl. 2):807, 1976. The spontaneous fibrinolytic activity of the blood is abnormally low significantly more often in persons with diabetes mellitus than in nondiabetic controls. The fibrinolytic response stimulated by venous occlusion is poor six times more frequently in diabetics than in controls, and the fibrinolytic activity of the endothelial cells is abnormally low in one-fourth of the diabetics tested. These changes are not related to the duration of diabetes. However, if patients with long-standing diabetes (> 10 years) are separated into those with retinopathy and those without, it is found that those who remain free from ophthalmoscopically visible retinopathy have an almost normal fibrinolytic response on stimulation, while the others have a significantly lower response. This difference seems to be caused by a faulty plasminogen activator release mechanism. Compared with the other diabetics, those with retinopathy also have a significantly increased level of fibrinogen and of O!2-macroglobulin, a protein that acts as an inhibitor of fibrinolysis. These findings imply a poor defense mechanism against fibrin deposits in the vessel walls in diabetes, which might contribute to the development of diabetic microangiopathy. Aimer, L. 0.; Pandolfi, M.; and Osterlin, S. (Coagulation Lab., Dept. ofOphthal. and Dept. of Intern. Med., Univ. of Lund, Malmo, Sweden): THE FIBRINOLYTIC SYSTEM IN PATIENTS WITH DIABETES MELLITUS WITH SPECIAL REFERENCE TO DIABETIC RETINOPATHY. Ophthalmologica (Basel) 270:353, 1975. The fibrinolytic system has been studied in 168 patients with diabetes mellitus (DM) and compared to that of a group of 153 sexand age-matched control subjects. The following determinations were made: spontaneous fibrinolytic activity of the blood; fibrinolytic response to standardised venous stasis (stimulated fibrinolytic activity, 'fibrinolytic capacity'); histochemical determination of fibrinolytic activators in the walls of superficial veins collected by biopsy. Diabetic patients were found as a group to have an impaired fibrinolytic system with the above fibrinolytic parameters decreased to various degrees in comparison with those of the controls. Less clear differences were observed between patients with and without ophthalmoscopically visible diabetic changes of the retina. However, patients with beginning angiopathy were found to have a significantly higher amount of fibrinolytic activators in their vessel walls than patients with more advanced retinopathy and without ophthalmoscopically detectable retinopathy. Furthermore, unlike patients without retinopathy, patients with retinopathy increased less or did not increase at all their spontaneous and stimulated fibrinolytic activity along the duration of the disease. The defective fibrinolytic system of diabetic patients may contribute to the occurrence of the vascular complications frequently seen in this disease. In the diabetic group, those patients who develop retinopathy show an impaired fibrinolytic defense with the duration of the disease. Bensoussan, D.; Levy-Toledano, S.; Passa, P.; Caen,J.; andCanivet, J. (Dept. of Endocrin. and of Haemostasis and Exper. Thrombosis, Univ. Paris-VII, Hosp. Saint Louis, Paris, France): PLATELET HYPERAGGREGATION AND INCREASED PLASMA LEVEL OF VON WLLLEBRAND FACTOR IN DIABETICS WITH RETINOPATHY. Diabetologia 22:307, 1975. In 18 insulin-dependent diabetics (6 without retinopathy, 6 with proliferative retinopathy and 6 with proliferative retinopathy treated by hypophysectomy) matched for age and duration of diabetes, in vitro haemostasis was studied using ADP induced platelet aggregation, ristocetin induced platelet aggregation which allows von Willebrand factor (VIII VWF) assay, and de350 DIABETES, VOL. 2 7 , NO. 3
TL;DR: Endocrine-cell populations in the islets of Langerhans of mutant mice with a severe hypoinsulinemic diabetes or with a mild hyperins insulinemic diabetes were studied quantitatively and induced a qualitative alteration of cellular interrelationships in the affected islets.
Abstract: Endocrine-cell populations in the islets of Langerhans of mutant mice with a severe hypoinsulinemic diabetes ( obiob or dbldb on the C57BL/KsJ background) or with a mild hyperinsulinemic diabetes ( ob/ob or db/db on the C57BL/6J background) were studied quantitatively by immunofluorescence and morphometry. In severely diabetic mice, islets presented a reduced proportion of insulin-containing cells buf increased glucagon-, somatostatin-, and pancreatic polypeptide (PP)-containing cells, as compared with islets of control (+/+) mice. An inverse change was observed in islets of mildly diabetic mice: islets were hypertrophie and composed mostly of insulin-containing cells, with decreased proportions of glucagon-, somatostatin-, and PP-containing cells. In both types of diabetic syndromes, the changes in cell populations induced a qualitative alteration of cellular interrelationships in the affected islets.
TL;DR: Low serum magnesium concentration was measured in 71 insulin-treated diabetic outpatients who had had the disease for 10 to 20 years and appears to be an additional risk factor in the development and progress of this complication.
Abstract: The serum magnesium concentration was measured in 71 insulin-treated diabetic outpatients who had had the disease for 10 to 20 years. The patients were divided into two subgroups according to the severity of their retinopathy. As a whole the patients exhibited a definite hypomagnesemia (P
TL;DR: The clinical and etiologic heterogeneity of diabetes in man is discussed, which appears to consist of a number of heterogeneous syndromes characterized by a continuum of metabolic changes secondary to insufficient insulin action and by various tissue changes referred to as the chronic complications of diabetes.
Abstract: We have chosen to discuss the clinical and etiologic heterogeneity of diabetes in man, since in recent years there has been an accumulation of evidence from many centers, including our own, that idiopathic or primary diabetes mellitus is not a single disease entity What we call diabetes mellitus appears to consist of a number of heterogeneous syndromes characterized by a continuum of metabolic changes secondary to insufficient insulin action and by various tissue changes referred to as the chronic complications of diabetes
Journal Article•
TL;DR: The data suggest that the hypercalciuria of uncontrolled diabetes may be a form of renal hyperCalciuria which could result in parathyroid stimulation which might contribute to the development of osteopenia in patients with diabetes mellitus.
Abstract: Calcium and phosphous metabolism was investigated in 20 patients with diabetes mellitus when their diabetes was under poor metabolic control and again once optimal glycaemic control was achieved with aggressive insulin therapy. Ten of the twenty uncontrolled diabetics had hypercalciuria; insulin therapy returned calcium excretion to normal in five. Twenty-four hour calcium excretion fell in all but two patients when optimal diabetic control was achieved and calcium excretion was positively correlated with glucose excretion. Urinary cyclic AMP excretion, which was in the high normal range during poor control, decreased significantly during optimal insulin therapy. These data suggest that the hypercalciuria of uncontrolled diabetes may be a form of renal hypercalciuria which could result in parathyroid stimulation which might contribute to the development of osteopenia in patients with diabetes mellitus.
TL;DR: Vitreous fluorophotometry quantitatively measures breakdown of the blood-retinal barrier, possibly the earliest detectable ocular vascular abnormality in juvenile diabetic patients.
Abstract: Vitreous and aqueous humor fluorescein concentrations were measured one hour after graded intravenous fluorescein was given to 20 juvenile diabetics, ages 20 to 40, with and without ret-inopathy, and to 12 controls of similar age. Vitreous fluorescein concentrations were significantly higher in diabetics, indicating breakdown of the blood-retinal barrier. Mean vitreous fluorescein values were 10.66 ± 0.65 for the diabetics and 4.28 ± 0.37 ng./ml. for the controls. Breakdown of the blood-retinal barrier was also confirmed in diabetics under the age of 20 without retinopathy. The blood-aqueous barrier was similarly altered in diabetics. Vitreous fluorophotometry quantitatively measures breakdown of the blood-retinal barrier, possibly the earliest detectable ocular vascular abnormality in juvenile diabetic patients.
TL;DR: It is concluded that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism and appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.
Abstract: Clonidine is an antihypertensive drug that markedly suppresses plasma catecholamine levels. In an attempt to investigate the effects of suppression of endogenous catecholamine secretion on glucose homeostasis and glucoregulatory hormones, we administered oral clonidine to 20 normal male subjects, two patients with transsections of the cervical spinal cord, and one patient with an insulinoma. Unexpectedly, after a single dose of 0.5 ing. given to normal subjects, insulin concentrations fell and plasma glucose rose 12 ± 1 mg./dl. (p We conclude that clonidine causes hyperglycemia and inhibits insulin secretion through an alpha-adrenergic mechanism. Since plasma catecholamine concentrations and vascular tone were markedly reduced by clonidine, this drug appears to selectively stimulate metabolic adrenergic pathways different from those operative in vasomotor regulation.
TL;DR: In maturity-onset diabetics net splanchnic glucose output is increased after glucose ingestion, suggesting that a greater proportion of an oral glucose load enters the systemic circulation than in healthy controls.
Abstract: To determine the extent to which altered splanchnic glucose balance contributes to postprandial hyperglycemie in diabetes, splanchnic glucose exchange was determined in seven maturity-onset diabetics and 10 healthy control subjects in the basal state and for three hours following oral ingestion of 100 gm. of glucose. In the basal fasting state, arterial glucose levels in the diabetics (153±24 mg./100 ml.) were 75 to 80 mg./100 ml. higher than in controls while splanchnic glucose output was similar in the two groups (132 to 145 mg. per minute). Following glucose ingestion, arterial glucose concentration in the diabetics rose to peak levels (295 ±35 mg./100 ml.) that were 55 per cent higher than in controls and remained 100 to 125 mg./100 ml. above basal levels and 150 to 200 mg./100 ml. above control levels three hours after glucose. Splanchnic glucose output rose rapidly in the diabetics to values four times the basal rate at 15 to 30 minutes after glucose feeding and remained 60 per cent or more above basal levels throughout the three-hour period. In contrast, in the controls following a similar early rise, splanchnic glucose output returned to basal levels by 90 minutes. As a consequence, total splanchnic glucose output over three hours in the diabetics (53±4 gm.) was 33 per cent greater than in controls. In addition, the increment in splanchnic glucose output above basal levels in the diabetics (30±5 gm.) was 100 per cent greater than in controls and could account for 75 per cent of the augmented glucose accumulation in body fluids observed at three hours. It is concluded that in maturity-onset diabetics (1) net splanchnic glucose output is increased after glucose ingestion, suggesting that a greater proportion of an oral glucose load enters the systemic circulation than in healthy controls; (2) failure of splanchnic glucose retention is the major factor responsible for postprandial hyperglycemie in maturity-onset diabetes.
TL;DR: The Intranasal application of an Insulin solution in dogs resulted in the rise of plasma immunoreactive insulin and in dose-dependent hypoglycemie and the absorption of insulin from this site was found to be enhanced when insulin was dissolved in an acid medium.
Abstract: The Intranasal application of an Insulin solution in dogs resulted in the rise of plasma immunoreactive insulin and in dose-dependent hypoglycemie. The absorption of insulin from this site was found to be enhanced when insulin was dissolved in an acid medium. In addition, when an insulin preparation with some surfactant was used, the effectiveness of nasally administered insulin was 25 to 30 per cent of that achieved with intravenously administered insulin.
TL;DR: A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results and suggests that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level.
Abstract: Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.
TL;DR: Cell quantitation of F-cells in both species correlated significantly with the tissue concentration of PP in all regions studied, validating the use of morphometric techniques to quantitate the regional distribution of PP.
Abstract: The regional concentrations of pancreatic polypeptide (PP), insulin, and glucagon and the cellular distribution of PP were studied in 13 human and nine canine pancreases by radioimmunoassay, immunoperoxidase localization, and cell quantitation. PP concentration was highest in both the uncinate process and the head of the human pancreas and in the right lobe of the canine pancreas. In contrast, glucagon and insulin levels were higher in the body and tail of both the human and canine pancreases. Human F-cells, which contain PP, were located primarily at the periphery of the islets, although a few F-cells were scattered throughout the ducts and acini. Canine F-cells were located in ducts, acini, and islets; the relative proportion of canine F-cells in the endocrine and exocrine tissues differed according to location. Cellular quantitation of F-cells in both species correlated significantly with the tissue concentration of PP in all regions studied, validating the use of morphometric techniques to quantitate the regional distribution of PP.
TL;DR: A curve describing a nonenzymatic saturable model was found to fit the data of the two groups combined, suggesting the possible existence of a saturable system for glycosylation in man.
Abstract: Concentrations of glycosylated hemoglobin (GHb) are elevated in diabetes mellitus and are believed to reflect previous metabolic control. To better define possible determinants of GHb in man, we investigated the relationship between GHb and both fasting plasma glucose (FPG) and basal insulin (IRI) in 42 normal subjects and 29 patients with maturity-onset diabetes. Concentrations of GHb in diabetic subjects (12.7 ± 3.4, x ± S.D., per cent total hemoglobin) were significantly higher than in normal subjects (8.2 ± 1.2, p
TL;DR: Exogenous insulin administration, with maintenance of euglycemia, results in significant inhibition of basal insulin secretion; the administration of exogenous insulin for 60 minutes before and for60 minutes after the acute induction of hyperglycemia results insignificant inhibition of glucose-stimulated insulin secretion.
Abstract: To investigate whether insulin exerts feedback regulation of its own secretion, paired studies were performed in normal men in two separate protocols. In the first protocol, four men were studied on two occasions. On one occasion, insulin was infused at 5 μU. per kilogram per minute for 120 minutes, achieving arterial insulin levels of 600 to 700 μU./ml. With use of a variable glucose infusion, the plasma glucose concentration was maintained at fasting levels for 60 minutes and then raised abruptly to 165 mg./dl. and was maintained at that level for the remaining 60 minutes. On a second occasion, the study was repeated except that saline was infused instead of insulin. The plasma glucose concentration remained at fasting levels until the last 60 minutes, when it was similarly raised to 165 mg./dl. and maintained at that level until the end of the study. Connecting peptide reactivity (CPR) was measured as an index of endogenous insulin secretion in the presence of exogenous insulin. During the initial 60 minutes of the study, with euglycemia maintained, there was a significant (46 per cent) decline (p < 0.01) in the levels of CPR in the insulin-treated subjects. At 60 minutes, when hyperglycemia was induced, CPR rose in both groups. The rise of CPR in the insulin-treated group, however, was significantlyless (p < 0.01) than in the saline control group.
To investigate whether insulin inhibition of insulin secretion during hyperglycemia would occur without prolonged insulin pretreatment, paired studies were performed in three additional men. In this protocol, insulin (5 mU. per kilogram per minute) or saline was infused for 70 minutes. Euglycemia was maintained for just 10 minutes. Thereafter, the plasma glucose concentration was. raised to 170 mg./dl. in both groups. This acute induction of hyperglycemia without prolonged insulin pretreatment resulted in similar increases in CPR in both insulin- and saline-treated groups.
From these data we conclude that (1) exogenous insulin administration, with maintenance of euglycemia, results in significant inhibition of basal insulin secretion; (2) the administration of exogenous insulin for 60 minutes before and for 60 minutes after the acute induction of hyperglycemia results in significant inhibition of glucose-stimulated insulin secretion; and (3) exogenous insulin administered for just 10 minutes before and during the acute induction of hyperglycemia, however, does not result in inhibition of the insulin response to the hyperglycemic stimulus.
TL;DR: It is hypothesized that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15, and greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.
Abstract: The concept that idiopathic diabetes mellitus is a genetically heterogeneous group of disorders has been established by twin and HLA studied that have permitted the separation of juvenile-onset and maturity-onset diabetes. The extent of the heterogeneity within the juvenile-onset and maturity-onset types is still in question. On the basis of recent immunologic and metabolic studies we believe that further heterogeneity can be demonstrated within the juvenile-onset diabetic group. We wish to hypothesize that there are at least two distinct forms of juvenile-onset diabetes, one associated with HLA B8 and the other with BW15. The B8 type is characterized by autoimmunity, microangiopathy, and a stronger association with the HLA D locus. The BW15 type is characterized by antibody response to exogenous insulin and a stronger association with the HLA C locus. Greater understanding of the pathogenesis, natural history, and genetics of diabetes mellitus will result as the full extent of genetic heterogeneity is elucidated.
TL;DR: The influence of the age at onset as well as the duration of disease on the prevalence of residual beta-cell function was studied in insulin-dependent diabetic patients, finding the prevalence was almost 100 per cent during the first two years of disease and was lower thereafter in diabetics with early onset.
Abstract: The influence of the age at onset as well as the duration of disease on the prevalence of residual beta-cell function was studied in insulin-dependent diabetic patients. Two hundred and sixty-seven patients presented at an early age (10–19.9 years) and 158 patients had a late onset (30–39.9 years of age). Beta-cell function was evaluated by measuring serum C-peptide immunoreactivity. Fifty-six patients (21.0 per cent) in the early-onset group and 64 (40.5 per cent) in the late-onset group had residual beta-cell function. The prevalence of residual beta-cell function was almost 100 per cent during the first two years of disease and was lower thereafter in diabetics with early onset. About 15 per cent of all patients with a duration between 15 and 35 years had residual beta-cell secretory function.