Showing papers in "Diabetologia in 1978"

Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.

Abstract: The diabetes syndromes produced by the two single gene mutations, obese (ob), and diabetes (db) are identical when both genes are expressed on the same inbred background, whereas on different backgrounds the syndrome changes from a severeobesity, moderate-diabetes to a severe life-shortening diabetes. The same initial sequence of events occurs in both conditions. Increased secretion of insulin and hyperphagia is followed by moderate hyperglycaemia with a further compensatory increase in insulin secretion followed by an expansion of the beta-cell mass. On the BL/6 inbred background, hypertrophy and hyperplasia of the beta cells continues until hyperglycaemia is controlled, whereas on the BL/Ks background, beta cell expansion fails and islet atrophy occurs causing insulinopenia, marked hyperglycaemia, and severe diabetes. The data presented here suggest that hyperphagia, hyperinsulinaemia, or both, early in development trigger the abnormal sequence of metabolic events leading to the obesity-diabetes state. These primary events interact with unknown genetic modifiers to produce either a juvenile or maturity-onset type of diabetes. An understanding of the mode of action of these background modifiers influencing the severity of diabetes in mice should lead to a better understanding of the ways in which unknown genetic and environmental factors contribute to human diabetes.

Prognosis of diabetics with diabetes onset before the age of thirty-one. I. Survival, causes of death, and complications

Abstract: In 307 patients with diabetes mellitus, developed prior to 1933 and before age 31 it was demonstrated that: (1) frequent contact with a specialized diabetes clinic from an early stage of the disease; (2) a good quality of “metabolic control”; (3) a low insulin dose; (4) a body weight of 10% less than ideal; and (5) a mean blood pressure below 100 mm Hg, all had significantly beneficial effects upon the survival. It was also found that patients domiciled in Copenhagen had a significantly better prognosis than patients domiciled outside Copenhagen. Frequent contact with a diabetes centre was accompanied by an appreciable decrease in disabling late diabetic complications.

Relation of diabetic control to development of microvascular complications.

Abstract: This review seeks to supply the arguments which support or deny the relationship between the quality of control of blood glucose levels and the course of diabetic microangiopathy. The ideal study is impossible to do in man but most prospective studies suggest that the better the control the slower the rate of progression and severity of lesions. “Scientific” but indirect arguments from biochemical, enzymatic and functional studies have shown that insulin and/or blood glucose control reverse some early diabetic changes that are probably related to the late events. Recent studies suggest that observations on animals that have shown the beneficial effect of treatment are relevant to the problem of diabetic microvascular lesions in man. Heredity influences the development of diabetic microangiopathy in diabetics but retinal and/or glomerular lesions — which are definitely not pathognomonic for diabetes — do not appear in the absence of hyperglycaemia. Muscle capillary basement membrane thickening that seems not to be a specific abnormality was not observed by several investigators in recently diagnosed diabetics. Therefore most of the arguments that have been given to support the point of view that tight control is not justified may be rejected. The opinion of the author is that strict control of diabetes is worthwile in patients with long life expectancy and no psychological, social or cultural handicaps.

Isolated mouse pancreatic islets in culture: effects of serum and different culture media on the insulin production of the islets.

Abstract: Various conditions for tissue culture of collangenase-isolated mouse pancreatic islets were studied in an attempt to optimize the maintenance of glucose stimulated insulin biosynthesis and release in the cultured specimens. Islets which had been cultured at a physiological glucose concentration (5.5 mmol/1) in the absence of serum had an impaired glucose-stimulated insulin biosynthesis and release as well as a reduced insulin content. Thus, insulin biosynthesis was three times higher after culture in a serum supplemented medium. Further, the insulin secretion of islets cultured in the presence of serum was markedly enhanced in acute incubations with high concentrations of glucose. This response was most pronounced in islets which had been cultured free-floating. A comparison between different culture media showed that islets cultured in RPMI 1640 had the highest insulin production. The present data suggest that the most favourable conditions for long-term storage of isolated islets in culture may be obtained when the islets are maintained as free-floating explants in a culture medium consisting of RPMI 1640 supplemented with serum.

The influence of amyloid deposits on the islet volume in maturity onset diabetes mellitus.

Abstract: Pancreatic islet volumes of patients with and without maturity onset diabetes mellitus were estimated. The islet volume of the diabetic patients was 1.01±0.12 cm3 (SEM) and that of the nondiabetic patients 1.60±0.16 cm3 with considerable overlap between the two groups. Islet amyloidosis was found in all the diabetic and in 9 of the 15 nondiabetic patients. When the amyloid deposits were excluded, the islet volume of the diabetic patients was 0.89±0.10 cm3, while that of the non-diabetic patients was unchanged, 1.60±0.16 cm3. There was still some overlapping. Since amyloid deposits seem to destroy the B cell membranes, it was postulated that a comparison of the volumes of islets completely free of amyloid might give a more true picture of the quantitative islet alterations in maturity onset diabetes. It was found that this islet volume of the diabetics was only 0.41±0.05 cm3 and that of the nondiabetic patients 1.58±0.16 cm3. These values correspond better to the altered insulin secretion in maturity-onset diabetes mellitus.

The spontaneously diabetic Wistar rat (the "BB" rat). Studies prior to and during development of the overt syndrome.

Abstract: A longitudinal study of 51 weanlings from 5 litters of “BB” Wistar rats was undertaken to characterize the time course of the spontaneous diabetic syndrome. Nine rats developed overt diabetes. An abnormal glucose tolerance preceded the onset of the syndrome in 6 of these 9 rats. No other “clinical” or metabolic variable measured was predictive of the development of this syndrome. In these rats, the onset was remarkably abrupt, followed by rapid clinical deterioration with marked hyperglycaemia, glycosuria, ketonaemia and hypoinsulinaemia attained within 2 to 8 days. Pronounced insulitis was present in the early stages of the syndrome, resulting in complete B-cell destruction at the time of sacrifice at 7 to 40 days. Among the 42 littermates, 9 revealed sequential abnormalities in oral glucose tolerance tests performed at weekly intervals (to age 90–120 d) though remaining aglycosuric and maintaining normal fasting plasma glucose levels. In 7 of these rats, a milder form of the same islet inflammatory lesion seen in the overtly diabetic animals was present. Thus the new features identified are: 1) a time course of evolution from normoglycaemia to overt diabetes telescoped into a period of days, and 2) a “chemical” stage or form with an insulitis similar to that found in the early stages of overt diabetes.

Lactic acidosis in biguanide-treated diabetics: a review of 330 cases.

Abstract: The paper presents an analysis of clinical symptoms, signs and laboratory data of 330 diabetic patients who developed lactic acidosis after having been treated with biguanides (phenformin, buformin, metformin). From the review of the literature an attempt is made to find special features that predisposed patients to develop lactic acidosis such as accompanying illnesses and additional medications, to describe the course of illness and also the factors that influenced the prognosis. Of the patients that developed lactic acidosis 50.3% died. These patients were older, they suffered more frequently from cardiovascular shock, their acidosis was more severe, the whole blood lactate concentration was higher, and the degree of renal insufficiency was more advanced. From our observations we conclude that the treatment of diabetes mellitus with biguanides should be reserved for specially selected patients.

Gastric inhibitory polypeptide (GIP) and insulin in obesity: Increased response to stimulation and defective feedback control of serum levels

Abstract: To investigate the possibility that an abnormality of the entero-insular axis is responsible for the hyperinsulinaemia of obesity, serum immunoreactive gastric inhibitory polypeptide (IR-GIP) and insulin (IRI) were measured after the ingestion of a liquid mixed test meal, glucose or fat, in normal weight and obese subjects. The latter were divided into a group with normal oral glucose tolerance (nOGT) and a group with pathological glucose tolerance (pOGT). Fasting levels of IR-GIP were significantly elevated in the obese group with pOGT. After the mixed meal the overweight subjects showed a significantly greater response of IR-GIP than the controls, with highest levels in the pOGT group. Simultaneously, the IRI response was significantly greater in the obese subjects than in the controls. The increases of IR-GIP and IRI after an oral load of 100 g glucose were normal in the obese subjects, but showed a significantly greater integrated response in the obese patients with pOGT. The ingestion of 100 g fat induced no IRI release but a significantly greater release of IR-GIP in the obese subjects, irrespective of their glucose tolerance. It is concluded that fat is a stronger releaser of IR-GIP than glucose. The effect of a combined load of glucose (30 g) and fat (100 g) was also compared in obese and normal weight subjects with the effect of either alone. Fat but not glucose released significantly more IR-GIP in obese subjects. In normal weight controls, but not in obese subjects, the IR-GIP release after fat plus glucose became significantly smaller than after fat alone. Since only the combined ingestion of glucose and fat and not fat alone releases insulin it is suggested that endogenous insulin inhibits GIP release and that this feedback control between insulin and GIP is defective in patients with obesity.

Haemoglobin A1 and Diabetes Mellitus

Abstract: HbA1c is the product of a reaction between glucose and the N-terminal valine of adult haemoglobin (HbA). The levels of HbA1c are increased in diabetic patients, and reflect their metabolic control. Thus, measurements of HbA1c have proved to be useful in the follow up and treatment of diabetic patients. HbA1c may prove to be valuable for assessing the relationship between diabetic control and long-term complications, as well as in studying the potential glycosylation of proteins in various organs which may occur in the diabetic state.

Type I diabetes mellitus

Abstract: The major genetic susceptibility to insulin dependent (Type 1) diabetes is determined by genes in the HLA chromosomal region. An increased relative risk for developing the disease is observed in subjects who are HLA A1, A2, B8, B18, B15, B40, CW3, Bfs, DW3, DW4, DRW3, DRW4 positive. There is an additive relative risk in subjects who possess two “high risk” HLA B alleles which has an important influence on the prevalence of the disease in sibships and possibly on the concordance rate in diabetic identical twins. There is also suggestive evidence that particular combinations of “high risk” HLA B alleles are associated with increased or persistent antibody production which may reflect enhanced or differential susceptibility. Certain factors (e. g. HLA B7, DW2 and DRW2) are associated with a significantly reduced risk and may exert a “protective” mechanism in Type I diabetes, by linkage disequilibrium with genes which reduce immune responsiveness. The significant increases and decreases in respect of the HLA B antigens are probably secondary to the corresponding HLA D and DRW associations which reflect a stronger linkage disequilibrium between the genes which determine these specificities and the putative genes which control susceptibility. Initial damage to the beta cells probably occurs a considerable time before the onset of symptoms and theoretically modification of the immune response early in the disease process may reduce the rate of beta cell destruction.

Prognosis of diabetics with diabetes onset before the age of thirty-one. II. Factors influencing the prognosis.

Abstract: In 307 patients with diabetes mellitus, developed prior to 1933 and before age 31 it was demonstrated that: (1) frequent contact with a specialized diabetes clinic from an early stage of the disease; (2) a good quality of "metabolic control"; (3) a low insulin dose; (4) a body weight of 10% less than ideal; and (5) a mean blood pressure below 100 mm Hg, all had significantly beneficial effects upon the survival. It was also found that patients domiciled in Copenhagen had a significantly better prognosis than patients domiciled outside Copenhagen. Frequent contact with a diabetes centre was accompanied by an appreciable decrease in disabling late diabetic complications.

A rapid micro-scale method for the measurement of haemoglobin A1(a+b+c)

Abstract: A rapid method is described for the measurement of total glycosylated haemoglobins (HbA1(a+b+c). The procedure utilizes 0.05 ml of blood and takes forty minutes to complete manually. Eighty blood samples can be analysed without automation by one person in a day. Each analysis uses less than 2 mg of potassium cyanide, resulting in a method that is both safe and rapid for routine hospital laboratories. The inter-assay coefficient of variation was 4% and that for intra-assay measurements 3%, over the range 5–20% HbA1(a+b+c). The method confirmed that the level of HbA1(a+b+c) is elevated in imperfectly controlled diabetics. Amongst patients with blood glucose levels of less than 10 mmol/l the mean level of HbA1(a+b+c) was found to be 8.5%; samples from 14 known diabetics gave a mean value of 10.9%, whereas 17 known non-diabetic samples gave a mean value of 8.3%. In the group of samples from 27 diabetic individuals with blood glucose levels above 10 mmol/l the mean level of HbA1(a+b+c) was found to be 13.5%.

The Endocrine Pancreas of the Fetus from Diabetic Pregnant Rat

Abstract: Diabetes was induced in female rats by streptozotocin administration prior to mating. Pregnant rats were divided into “severe diabetics” (blood glucose concentration above 300 mg/100 ml) and “mild diabetics” (blood glucose ranging from 100 to 200 mg/100 ml). When compared to control fetuses, fetuses from severely diabetic mothers showed a slight decrease of body weight on days 20.5 and 21.5. Fetal pancreatic insulin stores and plasma insulin concentrations were decreased at 19.5, 20.5 and 21.5 days. The insulin response to glucose was impaired bothin vivo andin vitro. In contrast, fetuses from mildly diabetic females showed no change in body weight. Pancreatic and plasma insulin concentrations were increased at 19.5, 20.5 and 21.5 days. The response of theβ cells of term fetuses of mild diabetics to glucose stimulation was enhancedin vitro. These results are consistent with the hyperglycaemiahyperinsulinaemia theory with regard to the fetuses from mildly diabetic rats and with an impairment of insulin biosynthesis and release in fetuses from severely diabetic females.

Peripheral nerves in early experimental diabetes: expansion of the endoneurial space as a cause of increased water content.

Abstract: The aim of the present study was to examine whether the nerve water content and the Schwann cell cytoplasm are increased in early experimental diabetics, as suggested in the sorbitol theory. The sciatic nerves of streptozotocin diabetic rats were found to have an increased wet weight. The amount of Schwann cell cytoplasm was reduced by 30%. The increased wet weight was paralleled by enlargement of the cross sectional area of the nerve which was explained by an expansion of the endoneurial space. The findings indicate the existence of endoneurial oedema and are in part in conflict with the sorbitol theory. Extension of the space surrounding the nerve fibres may explain the increased resistance to ischaemia in diabetic patients.

Increased glomerular permeability to albumin induced by exercise in diabetic subjects

Abstract: The urinary excretion of albumin was measured in insulin-dependent diabetics under ordinary conditions of life and in response to exercise. Possible mechanisms of exercise induced albuminuria in diabetics were also investigated. Under ordinary conditions of life the insulin-treated diabetics, as a group, had a higher mean urinary albumin excretion than normal controls; however, half of the diabetics had albumin excretion rates within the control range. A given exercise load (600 kpm/min for 20 min) produced an exaggerated albumin excretion in diabetics, particularly evident in the post-exercise period. The elevated urinary albumin excretion was due to an increased transglomerular passage of albumin, not to reduced tubular reabsorption. The increase was not associated with differences in blood pressure or urine flow between controls and diabetics. This exercise test has proved to be a suitable provocation test to unmask abnormalities in the glomerular handling of albumin that might not be recognisable at rest.

Sustained insulin-induced remissions of juvenile diabetes by means of an external artificial pancreas

Abstract: Remission of diabetes was attempted in 12 recent acute onset ketosis-prone juvenile diabetes after short term (5±1 days) but excellent blood glucose control by the external artificial beta-cell. The comparison group comprised patients undergoing traditional treatment (n=28). Nine (75%) persistent (over 3–14 months of duration) although partial (oral drugs required) remissions were obtained in the former group as compared to 3 (11%) in the latter group (p<0.05). Cases which showed remissions after insulin infusion had a plasma insulin response to IV glucagon still present before insulin infusion, and a daily urinary C-peptide excretion significantly enhanced after (p<0.01). Urinary C-peptide /blood glucose remained improved during the remission period. Thus, early effective treatment by means of the artificial pancreas may break the vicious circle hyperglycaemia-insulin depletion-hyperglycaemia and lead to frequent and sustained remissions of juvenile diabetes.

Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas.

Abstract: The release of pancreatic polypeptide (PP) by gut hormones, acetyl choline and adrenaline was investigated in an isolated perfused pancreas preparation. PP was potently released by 1 nmol/1 caerulein (186 +/- 12%, p is less than 0.001) and gastric inhibitory peptide (GIP) (211 +/- 31%, p is less than 0.005) as well as by 1 mumol/1 acetyl choline (1097 +/- 59%, p is less than 0.001). A significant two-fold release of PP was also evoked by 1 nmol/1 vasoactive intestinal peptide (VIP) (129 +/- 38%, p is less than 0.02 and gastrin (108 +/- 25% p is less than 0.01). Insulin release, induced by high glucose concentration was enhanced by both GIP (210 +/- 38%, p is less than (0.01) and VIP (48 +/- 5%, p is less than 0.001). In addition GIP enhanced the release of glucagon by 179 +/- 18% (p is less 0.001) at 1.4 mmol/1 glucose and by 127 +/- 24% (p is less than 0.005) at 8.3 mmol/1 glucose. Thus no simple inter-relationship appears to exist between the control of the three circulating islet hormones.

Physical exercise and fuel homeostasis in diabetes mellitus.

Abstract: During the initial phase of physical exercise muscle glycogen is the primary source of fuel for contracting muscle in normal man. When exercise continues beyond the first 5–10 min blood glucose and free fatty acids (FFA) become increasingly important substrates. Glucose utilization may account for 25–35% of the total substrate supply during mild to moderately heavy exercise. The augmented glucose utilization by working muscle is balanced by a rise in hepatic glucose production. The latter is achieved primarily by hepatic glycogenolysis during brief work, but during prolonged exercise gluconeogenesis may account for as much as 40–50% of the hepatic glucose output. Muscle uptake of FFA is determined primarily by its availability to the working muscle, and it may account for 30–60% of the total fuel supply. Ketone bodies are not utilized by working muscle in normal man. In patients with diabetes mellitus the metabolic effects of physical exercise are to a large extent determined by the time interval between insulin administration and the onset of exercise. Thus, in insulin treated patients with mild hyperglycaemia and no or minimal ketonaemia the utilization of glycogen, blood glucose and FFA by working muscle is similar to that of healthy subjects, and exercise is accompanied by a fall in blood glucose levels. In contrast, patients with more marked hyperglycaemia and hyperketonaemia may respond to exercise with a further rise in both blood glucose and ketone body levels, reflecting augmented rates of hepatic gluconeogenesis as well as ketogenesis. The repletion of muscle and liver glycogen, which takes place for 24–48 h after exercise, requires — besides carbohydrate feeding — a minimum concentration of insulin. Glycogen resynthesis probably accounts for a major part of the empirically well established beneficial effect of physical exercise in diabetic patients. The above considerations underscore the importance of adequate insulin administration in connection with exercise in diabetic patients.

Osteopenia in insulin treated diabetes mellitus. Its relation to age at onset, sex and duration of disease.

Abstract: Bone mineral content was measured by photon absorptiometry in 215 insulin treated diabetic out-patients aged 7–70 years. As bone mass increases until the age of 20–25 years, patients were so selected that all remained within the same phase of bone mineral storage throughout the entire course of their diabetes. Other criteria for exclusion were diseases or drugs interfering with mineral metabolism and previous use of oral antidiabetic agents.

Developmental changes in the fatty (fafa) rat: evidence for defective thermogenesis preceding the hyperlipogenesis and hyperinsulinaemia.

Abstract: Preobese “fatty” rats have been identified by their lower rectal temperature. Of 51 pups born from matings of heterozygote (Fafa) parents, 16 had low rectal temperatures from day 16 onward (34.6±0.2° C v 35.4±0.3° C) and all subsequently became obese. No animal with the higher ‘normal’ rectal temperature developed obesity. Hepatic fatty acid synthesis (preobese 0.6±0.1; lean 0.6±0.1 μmol/ g/h), hepatic glucose-6-phosphate dehydrogenase activity (G6PDH) (preobese 0.68±0.07; lean 0.71 ±0.03 μmol/g/min) and serum insulin (preobese 64 ±2; lean 58±4 μU/ml) were unchanged in 18 day preobese, suckling fafa rats. 3 days after weaning hepatic lipogenesis (preobese 25.3±2.0; lean 5.4±0.7 μmol/g/h) and G6PDH activity (preobese 4.5±0.5; lean 0.90±0.05 μmol/g/min) had increased in both lean and preobese rats although the values attained in preobese rats were significantly greater than in lean rats. When weaning was delayed there was no enhancement in lipogenesis, G6PDH or serum insulin in the preobese rat. The results suggest that the primary genetic defect in ‘fatty’ rats is not related to the increase in lipogenesis or serum insulin but may reflect a defective thermogenic process.

Lipogenesis in situ in the Genetically Obese Zucker Fatty Rat (fa/fa): Role of Hyperphagia and Hyperinsulinaemia

Abstract: In situ fatty acid synthesis has been measured with 3H2O in anaesthetised lean and obese Zucker (fa/fa) rats. The accumulation of fatty acids was increased in both the liver and adipose tissue of young fa/fa rats as a result of both an increased rate of lipogenesis and an increase in tissue mass. Whereas total hepatic lipogenesis increased with age, total adipose tissue lipogenesis decreased in older fa/fa rats. Experiments with hepatectomized rats showed that the liver was the major site of the excess fatty acid synthesis in fa/fa rats. The enhanced rate of lipogenesis in fa/fa rats was abolished by either pair-feeding or streptozotocin treatment. The results suggest that the increased fatty acid synthesis in fa/fa rats is secondary to the hyperphagia, hyperinsulinaemia, and increased mass of hepatic and adipose tissues.

NSILA-carrier protein abolishes the action of nonsuppressible insulin-like activity (NSILA-S) on perfused rat heart

Abstract: Human serum in a concentration of 10% in the perfusion medium failed to increase glucose uptake by the isolated perfused rat heart, indicating that nonsuppressible insulin-like activity (NSILA) in whole serum was inactive in this system. When NSILA-carrier protein was added to partially purified NSILA-S, its biological activity on the rat heart disappeared. In contrast, the action of insulin was not affected by the presence of NSILA-carrier protein. Binding of125I-labelled NSILA-S to rat heart was inhibited by NSILA-carrier protein.125I-labelled insulin binding was not inhibited. These results support the hypothesis that NSILA-S bound to serum carrier protein is a large molecular compound which does not readily diffuse out of the capillary bed and therefore does not exert insulin-like effects in vivo.

Glomerular hyperfiltration during the onset of diabetes mellitus in two strains of diabetic mice (c57bl/6j db/db and c57bl/ksj db/db).

Abstract: GFR estimated by the total clearence of51Cr-EDTA increases from 41 to 60 ml/min·m2 at the onset and during the development of marked hyperglycaemia and obesity in female diabetic mice (db/db) of the C57BL/6J and the C57BL/KsJ strains (blood sugar rises from 160 to 400 mg/100 ml). GFR decreases slowly in older diabetic mice (>120 days old) approaching the control values (42±7 ml/ min·m2) and then decreases still further. The total clearance of14C-hippuric acid is unaltered indb/db mice and controls between 45 and 150 days of age (96±20 ml/min·m2). This suggests no alteration of RPF during the development of the diabetic syndrome. The glomerular hyperfiltration of diabetic mice lasts until they are 120 days old and shows no correlation with the different blood glucose levels typical for diabetic mice (db/db) of the two strains.

Effect of insulin on amino acid transport in isolated rat hepatocytes

Abstract: The effects of insulin on amino acid transport were studied in freshly prepared suspensions of isolated hepatocytes from adult rats. Insulin stimulated the active transport of α-aminoisobutyric acid by increasing the influx. The onset of the insulin effect was delayed by thirty to sixty min. Insulin increased the Vmax of transport by about 60% without affecting the Km. Cycloheximide and actinomycin D inhibited hormonal action by 60 to 80%. Only the “A” system of transport was affected by insulin. Half-maximal stimulation of transport was observed with insulin at 2 to 3nmol/l, a concentration which also occupies about 50% of insulin-specific binding sites at steady state. Insulin did not antagonize the stimulatory effect of glucagon on amino acid transport.

Thyroid hormones in insulin requiring diabetes before and after treatment.

Abstract: Thyroid hormones have been measured in normal subjects and insulin-requiring diabetic patients before and after treatment. Plasma thyroxine (T4) and 3, 3′, 5-triiodothyronine (T3) concentrations were both low in diabetics, with T3 frequently in the hypothyroid range, while 3, 3′, 5′-triiodothyronine (rT3) concentrations were elevated. All three returned to normal following treatment. T3 concentration was directly related to glucose utilization and metabolic clearance rate; and inversely related to plasma ketone body concentration. Thyroid hormone abnormalities in diabetes may reflect the degree of insulin-secreting capacity.

Effects of diet on the cellular insulin binding and the insulin sensitivity in young healthy subjects

Abstract: To ascertain whether the effects of diet on glucose tolerance and insulin sensitivity are mediated through changes of insulin receptors we have studied insulin binding to monocytes in 24 young volunteers (4 groups of 6) during 2 week periods of different dietary regimens. In group 1 and 2 the subjects had their usual diet plus 1000 kcal per day from sucrose or fat, respectively. Group 3 had an isocaloric diet with a low-sucrose content, while group 4 ate low-fat high carbohydrate diets. Before change of diet the total group of volunteers showed an inverse correlation between insulin binding and average daily sucrose intake (R = − 0.52, p 0.1). A rise of insulin binding (p 0.1). After the isocaloric, low-fat diet (group 4) no significant change of insulin binding occurred (p>0.1) whereas the insulin sensitivity increased (p<0.05). We conclude that diet and especially the dietary sucrose content affect insulin binding to human monocytes. Evidence is presented that changes of insulin sensitivity following hyperalimentation of sucrose may be induced through alterations of insulin receptors.

The effects of chlorpropamide and insulin on serum lipids, lipoproteins and fractional triglyceride removal.

Abstract: The effects of chlorpropamide on serum lipids, lipoproteins and fractional triglyceride removal have been studied over 12 months on 10 maturity onset diabetics not controlled on diet alone. Similar studies were carried out in 6 maturity onset diabetics who had failed to respond to sulphonylureas and 6 new insulin requiring diabetics. In the chlorpropamide treated patients there was an initial fall in serum and VLDL triglyceride but this effect was lost at 12 months. There was no change in fractional triglyceride removal. At 12 months there was a fall in LDL and a rise in HDL cholesterol. An initial improvement in glucose tolerance and insulin secretion was maintained at 12 months. In the insulin treated group the initial fall in serum and VLDL triglyceride was maintained at 12 months and was accompanied by an increase in fractional triglyceride removal. There was also a fall in LDL and a rise in HDL cholesterol at 12 months. The failure of chlorpropamide to maintain the reduction in serum and VLDL triglyceride could be of importance in the genesis of coronary heart disease in maturity onset diabetics. The fall in LDL and rise in HDL cholesterol found both with chlorpropamide and insulin might be beneficial.

Persistent insulin secretion, assessed by plasma C-peptide estimation in long-term juvenile diabetics with a low insulin requirement.

Abstract: In order to investigate whether patients with long-standing juvenile diabetes mellitus (onset of diabetes before the age of 30) and a low daily insulin requirement (less than 0.50 units/kg body weight) still have functioning B-cells, plasma C-peptide was determined after stimulation (OGTT and glucagon/tolbutamide) in 64 patients with diabetes of more than 18 years' duration (mean 31 years). Measurable endogenous insulin production was found in 24% of the patients. The prevalence of severe retinopathy was lower in the secretors than in the non-secretor group. There was no difference in insulin antibody concentration between the two groups. Furthermore, the insulin requirement in the secretor group was relatively constant during the course of diabetes. Metabolic control was similar in both groups. It is concluded that a persisting but low activity of endogenous insulin production can be found in many long-term juvenile diabetics with a low insulin requirement, while others without any residual beta-cell function develop a low insulin requirement for unknown reasons.

Thickening of glomerular basement membrane in spontaneously diabetic rats.

Abstract: The glomerular basement membrane of spontaneously diabetic rats was investigated by quantitative analysis using electron microscopy, with special reference to the effect of ageing. Constant age-related increase in the width of basement membrane was ascertained both in diabetic and control rats, and the mean values of basement membrane thickness were always higher in the spontaneously diabetic rats than in normal control rats. Significant thickening of glomerular basement membrane was found in the diabetic rats at 12 weeks of age, while younger diabetic rats had no definite increase. The difference in basement membrane thickness between diabetic and normal control rats became larger with increasing age.