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Circulating levels of insulin, proinsulin-like component, glucagon, growth hormone, and pancreatic polypeptide were measured in 12 patients with functioning insulinomas, and the suppressibility of serum insulin by somatostatin and diazoxide was assessed before surgical removal of the tumors. The hormone content of the tumors was evaluated by radioimmunoassay and by immunofluorescence and the structure of the tumor cells by electron microscopy. Based on these findings, we propose a new classification of insulinomas in two groups: group A is characterized morphologically by abundant well-granulated typical B-cells, trabecular arrangement of tumor cells, and uniform insulin immumofluorescence; functionally, these tumors are associated with a moderate elevation of proinsulin-like component and with an almost complete suppressibility of serum insulin by somatostatin and diazoxide. In contrast, tumors of group B are characterized by scarce well-granulated typical B-cells, a medullary-type histologie structure, and irregular insulin immunofluorescence; functionally these tumors show elevated circulating levels of proinsulin-like component and a marked resistance of insulin secretion to somatostatin and diazoxide inhibition. This way of separating human insulinomas in groups A and B represents a simplification of existing classifications and emphasizes the quantitative ultrastructure in relationship to suppressibility of insulin secretion. The proposed classification of human insulinomas in groups A and B, however, does not allow the assessment of the clinical or histopathologic malignancy of the tumors.

The effect of treadmill training on intravenous glucose tolerance and insulin sensitivity was investigated in Zucker rats (fafa). In 25-week-old fafa animals with the typical metabolic syndrome of massive obesity, glucose intolerance, hypertriglyceridaemia and insulin resistance, treadmill exercise of only very mild intensity was carried out for 6 weeks. The training programme induced a marked reduction in basal and post-glucose challenge plasma insulin levels and a slight but significant improvement of intravenous glucose tolerance. No alteration in insulin sensitivity of the isolated perfused hindquarter was demonstrable. In another study a 9-week training programme was started in 7-week-old fafa rats before the development of their metabolic syndrome. In the sedentary control animals glucose intolerance and insulin resistance developed during the study period; in the training group, both the deterioration of glucose tolerance and the decrease of insulin sensitivity were prevented. This study demonstrates in fafa rats that (a) in young animals physical training may prevent a genetically predisposed deterioration of glucose tolerance and insulin sensitivity and (b) in adult animals mild physical training may improve intravenous glucose tolerance and insulin sensitivity.

In blind studies the effects of a new alpha-glucosidase inhibitor (BAY g 5421) were tested in normal weight and overweight male volunteers after oral application of 75, 150, or 300 mg of BAY g 5421 or placebo per os before three standardized main meals of one day. Before and three hours after each meal blood glucose, serum insulin, and serum triglyceride levels were determined. In addition, safety studies were performed. BAY g 5421 induced a statistically significant, in part dose-dependent inhibition of the postprandial increase of blood glucose- and serum insulin levels. The reduction of the postprandial increase of serum triglyceride levels was variable. Routine blood chemistry and hematology tests have revealed no adverse side effects; but the application of the drug was frequently associated with intestinal effects, such as flatulence and diarrhea, which were substrate (carbohydrate) and, in part, dose-dependent.

Acarbose, an alpha-glucosidase inhibitor, lowers the glycemie excursion following the ingestion of carbohydrates, in particular, sucrose. This was confirmed with increasing doses of acarbose (0, 50, and 100 mg) and the causes investigated. The absorption of the glucose moiety of sucrose was determined from plasma tracer concentrations when overnight-fasted normal subjects received a 100-g oral sucrose load labeled with sucrose ([1-14C]glucose) and a simultaneous intravenous infusion of [3-3H] glucose. As the dose of acarbose given with the sucrose load was increased from 0 to 100 mg, the percentage of the load appearing in the peripheral circulation decreased from 90% to 62%. Malabsorption was confirmed by the appearance of breath hydrogen. Simultaneously, absorption time increased from 243 to 411 min. Maximal glycemie excursions were therefore lowered from 64 to 31 mg/dl. The plasma concentrations of gastric inhibitory polypeptide and insulin decreased with the acarbose dose so that the fractional disappearance rate of glucose also decreased. However, the concentrations of glucagon-like immunoreactivity (GLI) rose, confirming the ileal appearance of malabsorbed sucrose.

Non-glucoregulatory hormones (T4, T3, rT3, TSH and testosterone) were studied by radioimmunoassay in juvenile-type diabetics in moderate control and in ketosis due to insulin withdrawal and in age matched "normals" during a mild prolonged exercise test. The basal serum hormone levels revealed the following findings: Serum testosterone was markedly lower in diabetics than in normals ( 177 +/- 24 resp. 618 +/- 52 ng/dl). This is in contrast to other studies, but it may reflect decreased testicular function due to an early, clinically not apparent atherosclerotic disease. Serum T3 was significantly lower in diabetics than in normals (110 +/- 16 resp. 145 +/- 19), suggesting an early "low T3-syndrome" in juvenile-type diabetics. However, increased serum rT3 levels were not observed, and serum T4 and TSH were normal. Mild prolonged exercise had no major effects on these nonglucoregulatory hormones. In juvenile-type diabetics the degree of metabolic control had no influence on the response of the mentioned hormones. However, an increased cortisol/testosterone ratio in ketotic diabetics in the basal state with a further increase during exercise was demonstrated, indicating an aggravation of the catabolic state in these patients during exercise.

The effect of physical training on glucose tolerance in vivo and skeletal muscle glucose metabolism in vitro was investigated in normal rats. Treadmill running for 10 days up to 240 min/day led to a decrease of basal and glucose-stimulated plasma insulin levels without major alterations of the IV glucose tolerance (1 g/kg body weight). Swim training of two weeks' duration, i. e. exercise up to 2×75 min/ day, which did not induce significant changes in body composition, skeletal muscle glycogen levels or citrate synthase activity, resulted in a significant improvement of IV glucose tolerance and substantial reductions of basal and glucose-stimulated plasma insulin levels. Associated with this apparent improvement of insulin sensitivity in vivo, significant increases of the insulin-stimulated glucose uptake (+ 55%) and lactate oxidation (+ 78%) in vitro were found on perfusion of the isolated hindquarter of swim-trained animals. It is suggested that mild physical training can improve glucose tolerance and insulin sensitivity in normal rats, at least in part, due to an increase of insulin sensitivity of skeletal muscle glucose metabolism.

The effects of a new sulfonylurea (Ro 6-4563) have been studied on glucose tolerance, plasma insulin, lipids, and lipoprotein pattern in 29 patients with maturity onset diabetes. After 4 weeks of treatment 3 different reactions have been distinguished and are discussed: I. No response, viz. same glucose tolerance and insulin levels before and after treatment. II. Improved glucose tolerance without increased insulin levels. III. Improved glucose tolerance with higher insulin levels. Sulfonylurea treatment had no effect on plasma lipids or lipoprotein pattern. Clinically “good blood sugar control” could not be correlated with good lipid control. Response II supports the view that sulfonylurea compounds do not necessarily act by increasing plasma insulin levels.

Radioactivity in adipose tissue triglycerides was followed after giving an intravenous injection of 25 g of glucose with 50 μCi of U-14C-glucose to 12 obese and 7 control patients. Seventy-five minutes after injection the radioactivity could be measured with sufficient precision. Recirculation of label was probably small during this period. Total adipose tissue glucose uptake could therefore be estimated knowing the variation of adipose tissue triglyceride radioactivity in different selected regions, and total body fat, and was found to be only a few per cent of all assimilated glucose in the body. Triglyceride radio-activity per gram of adipose tissue was similar in obese subjects and controls. Consequently total adipose tissue label was higher in the obese. Triglyceride radioactivity per fat cell correlated positively with fat cell size which in turn correlated positively with plasma insulin concentration. During the two first weeks after injection adipose tissue triglyceride radioactivity increased after which it began to fall in some patients.

12 months therapy with acarbose in 143 type I and type II patients markedly improved the metabolic control, assessed by fasting and postprandial blood glucose determination. During 5 year acarbose treatment GIP levels were decreased and enteroglucagon levels were elevated. After withdrawal of the drug for one week GIP levels increased and enteroglucagon concentrations fell. Thus, GI-hormone changes were reversible after discontinuation of acarbose. Tolerability of acarbose was good and clinical chemistry and haematology parameters showed no changes after 1-5 years acarbose therapy. Approximately 60% of the patients had intestinal symptoms which subsided again for most patients after 1-4 weeks therapy with acarbose. Body weight remained unchanged. The glucosidase inhibitor acarbose is a new effective and safe therapeutic concept in the treatment of diabetes mellitus.

There is a close epidemiological association between obesity and elevated blood pressure for all age groups, although not every obese individual becomes hypertensive. In populations without age-related increases in body weight, an elevation of blood pressure with age is not seen. Mechanisms included in the development of hypertension in obesity are hyperinsulinemia, insulin induced sodium retention and increased sympathetic tone. Overnutrition with over intake of sodium and lack of physical exercise contribute to the metabolic syndrome of obesity. Thus, weight reduction by decreased energy uptake and increased physical exercise is recommended in the treatment of hypertension in obese patients. The resulting fall in insulin levels may lead to decreased sodium absorption in the kidney. Although treatment of obesity by weight loss decreases blood pressure substantially, a minority of patients do not respond to the weight loss. Blood pressure generally decreases before normal weight is achieved. Salt intake reduction does not appear to explain why weight reduction lowers blood pressure. Reduced levels of plasma renin activity, serum aldosterone levels, catecholamine levels and serum insulin levels may be involved in the blood pressure lowering associated with weight loss. Since the risk of cardiovascular disease in the hypertensive patient is not only determined by the blood pressure, an overall treatment which aims at reduction of other risk factors such as glucose intolerance and hyperlipoproteinemia is advocated. Thus, in any obese hypertensive patient normalization of excess body weight and increased physical activity appears to be the first and most important step of any rational therapeutic strategy.

Metabolic and hormonal effects of muscular exercise were studied in juvenile-type diabetics in relation to the prevailing degree of metabolic control and compared with those in healthy control subjects. Two groups of diabetic patients, one in moderate metabolic control and one in ketosis due to insulin withdrawal, were subjected to a 3 hour bicycle ergometer test of comparable, mild work intensity. In both groups of diabetics the exercise-induced rise in blood lactate was similar, but was significantly higher than in control subjects. Blood alanine levels showed a transient, significant rise in both diabetic groups, but not in controls. Blood concentrations of branch-chained amino acids remained unchanged. In the moderately controlled diabetics, exercise induced a marked fall of blood glucose and increases in blood levels of free fatty acids (FFA), ketone bodies and glucagon, which were comparable to the exercise effects in normal controls. In ketotic diabetics, however, exercise led to an additional rise in blood glucose concentration and to increases in ketone body, glucagon and cortisol levels. Significant correlations were found between the exercise effect on blood glucose and initial blood levels of glucose, FFA, ketone bodies and branch chained amino acids: pre-exercise values of above 325 mg/dl glucose, 1173 μmol/l FFA, 2.13 mmol/l ketone bodies and 0.74 mmol/l branch chained amino acids led to increased blood glucose levels on exercise, whereas below these limits glucose fell during the exercise test. These findings seem to be, at least in part, explained by the hypothesis of a permissive effect of insulin during stimulation of muscle glucose uptake by exercise. The increased circulating levels of glucagon and cortisol during exercise in ketotic diabetics might represent additional hyperglycaemic and, probably more important, lipolytic and ketogenic stimuli. The results suggest that in moderately controlled, non-ketotic diabetics blood glucose falls during exercise; in ketotic, relatively insulin deficient patients, muscular activity has adverse metabolic and hormonal effects: a further increase in blood glucose, plasma glucagon and cortisol and a rapid aggravation of ketosis.

In 1332 patients with different degrees of obesity (344 men, mean age 36 +/- 13 years, Broca Index 1.46 +/- 0.23; 988 women, mean age 37 +/- 13 years, Broca Index 1.67 +/- 0.30), cardiovascular risk factors (RF), serum HDL-cholesterol, and insulin levels were investigated. The most frequent RF was diastolic hypertension (68 per cent), followed by systolic hypertension (56 per cent), glucose intolerance (55 per cent), hypertriglyceridemia (31 per cent), hyperuricemia (19 per cent) and hypercholesterolemia (18 per cent). Only 9.4 per cent of the patients were without RF, and these patients were younger and less obese than patients with RF. Compared with controls, HDL-cholesterol levels were decreased in obese patients, however, the negative linear correlation between relative body weight and HDL-cholesterol levels was only significant in women, not in men. HDL-cholesterol levels were higher in women than in men. Serum insulin levels were correlated positively with relative body weight and negatively with age. Partial correlation analysis revealed a stronger influence of age than body weight on blood pressure, serum levels of total cholesterol, LDL-cholesterol, triglycerides and blood glucose levels. Uric acid levels correlated positively, and HDL-cholesterol levels negatively with relative body weight alone and not with age. On the basis of prevalence of RF, low serum HDL-cholesterol and high insulin levels, obese patients must be considered at high risk with respect to the development of cardiovascular disease.

In a double-blind quadruple cross-over study the effect of a new alpha-glucosidase inhibitor (BAY g 5421) on postprandial blood glucose, serum insulin, and serum triglyceride increases was tested in 24 male healthy volunteers. They received before a standardized breakfast 50, 100, or 200 mg of BAY g 5421 or a placebo per os. The dose-time-response relationships were calculated and the drug tolerance was assessed. There was a statistically significant inhibition of the postprandial increases of the blood glucose, serum insulin, and triglyceride values. Further analysis showed no dose-dependent effect of the drug on the blood glucose values, whereas the serum insulin and triglyceride values were affected in a dose-dependent fashion. The maximal inhibitory effect on the serum insulin levels occurred 69 min after breakfast and on the serum triglyceride levels 104 min after breakfast. One hundred and 200 mg of BAY g 5421 were equally inhibitory-effective on the serum insulin levels, whereas the highest dose used was markedly more effective on serum triglyceride values than lower doses. Based on these results, a dosage of 100--200 mg of BAY g 5421/meal is recommended for clinical trials in metabolic diseases.

In 500 obese patients (146 men, mean age 37 +/- 13 years, Broca index 147 +/- 24; 354 women, mean age 36 +/- 14 years, Broca index 151 +/- 28) cardiovascular risk factors (RF) were investigated. The most frequent RF was hypertension (71 per cent), followed by glucose intolerance (49 per cent), hypertriglyceridemia (31 per cent), hypercholesterolemia (22 per cent) and hyperuricemia (22 per cent). Only 12 per cent of the patients were without RF. These patients were younger and less obese than the patients with RF. The prevalence of RF increased with increasing age and overweight. Analysis revealed significant correlations between overweight and blood pressure, blood glucose, insulin and age. Significant correlations between age and hypertension, blood glucose cholesterol, triglycerides and overweight were detected. The correlation between overweight and the sum of all RF was higher (r = 0.35) than the one between age and the sum of all (r = 0.23). Obese patients had a high prevalence of RF. Increasing overweight and (to a lesser extent) age are both associated with increased prevalence of RF. On the basis of the prevalence of RF, patients with gross obesity (Broca index greater than around 150) were considered to be at a high risk in respect of coronary heart disease.

This paper describes systematic studies on the absorption kinetics of exogenous insulin from its subcutaneous tissue depot in 52 male nonobese volunteers (age 20–30 yr). Five experimental protocols were used: (1) effect of changing injection site, (2) effect of temperature change and local massage, (3) effect of aprotinin and human serum, (4) effect of mixing regular insulin with long-acting insulin preparations, and (5) effect of temperature change, muscular exercise, and local massage on the absorption of longacting insulin preparations. The fastest absorption of insulin occurred at the abdominal injection. Absorption after arm injection was faster than after thigh injection. A hot bath and local massage dramatically increased serum insulin levels in the first 90 min after injection; in contrast, a cold bath delayed absorption substantially. Both aprotinin and the subjects' own blood serum mixed with insulin caused a marked acceleration of the insulin absorption process. Absorption kinetics of two neutral regular insulins (Actrapid and Leo Regular) were virtually identical. Mixing Actrapid with Monotard caused higher serum insulin levels than the mixture of Leo Regular with NPH. A time lag of 5 min between the mixing of Actrapid and Monotard and the injection caused a delayed rise of serum insulin levels; in contrast, this delay could not be observed when Leo Regular and NPH were mixed. Volunteers performed bicycle exercise, applied a hot water bottle to the injection site, or rubbed the injection site 2 1/2 h after injection of long-acting insulin. Accelerated absorption of insulin was only observed after local massage of the injection site of Monotard, Leo NPH, and Mixtard. Local heat had no effect. Exercise caused only an increased absorption of insulin after the Mixtard injection but not after Monotard or NPH injection. These findings have clinical significance and should not be without potential benefit in the attempt to improve metabolic control in insulin-treated diabetic patients.

The effects of physical activity on blood glucose homeostasis in diabetes mellitus and the potential benefits of exercise in the treatment of diabetic patients, are reviewed. Mild physical exercise results in a fall of blood glucose levels in controlled diabetic patients; this acute effect of exercise might be used in particular to inhibit the rise of blood glucose seen in insulin-treated diabetics after food intake. In contrast, physical activity will further deteriorate the metabolic situation in decompensated diabetic patients by an increase in blood glucose and a rapid aggravation of ketosis. On the other hand exercise potentiates the blood glucose lowering effect of subcutaneously injected insulin; therefore precautions have to be taken in order to avoid hypoglycemia in insulin-dependent diabetics especially during and after more strenous exercise. In juvenile-type diabetes, physical activity can be used as an efficient therapeutic adjunct only in cooperative, well-instructed patients who are used to check their metabolic situation on a regular basis. Physical training increases the tissues' sensitivity towards (endogenous) insulin. Hence, in addition to the diet, training might represent the most appropriate treatment in maturity onset-type diabetic patients. However, direct evidence for an improvement of glucose tolerance in diabetic patients by physical training is still lacking. In order to formulate detailed, generally applicable recommendations on how to carry out a useful therapeutic program of physical exercise and/or training in diabetic patients, further clinical studies assessing the quantitative effects of physical activity on carbohydrate metabolism are needed.

In 6 normal weight juvenile diabetic patients treated with continuous subcutaneous insulin infusion (CSII) we have investigated whether the restrictive management of the diabetes diet could be relaxed. On 2-3 days of a 4 week period the patients ate a) a conventional diabetes diet consisting of 3 main meals and in-between snacks of a prescribed carbohydrate content or b) a liberal diabetes diet in which the patients could choose the number of meals and carbohydrate contents. With both diets, mean blood glucose levels during the day were in normal range (96 +/- 3 and 101 +/- mg/dl, mean +/- SEM). On the liberal diet meal frequency and carbohydrate intake per day were significantly lower, the carbohydrate content per meal significantly larger when compared with the conventional diabetes diet. There was not difference in insulin requirements per day (basal rate plus premeal dosage). All the patients preferred the liberal diet. CSII allowed juvenile diabetic patients a more liberal management of their diabetes diet without negative effects on blood glucose control. Hence CSII improved the quality of life in these patients.

Albeit physical exercise and training have been recommended as an integral part of diabetes therapy only limited data are available to prove such beneficial effects of physical exertion in normalizing the metabolism in diabetes. It is the purpose of this review to critically summarize studies concerning the effects of physical training in maturity-onset diabetes. Based upon available evidence in animal experimentation, i.e. in normal and fat ZUCKER rats, as well as on data in non-diabetic man, physical training is expected to increase peripheral insulin sensitivity; thus a decrease of insulin requirements might be achieved in the course of a physical training program. So far, however, the preliminary evidence of only two studies on the effect of training in maturity-onset diabetes has been presented: slight improvements of glucose tolerance and a considerable, but--at least in one study--short-lived decrease of circulating insulin levels have been described. These improvements have to be weighed against the possible hazards of physical training programs in maturity-onset diabetic patients who--as a group--have to be considered at high coronary risk. More and more detailed and prolonged studies, however, are urgently needed to document and to prove beyond any doubt the benefits of physical training in the metabolic syndrome of maturity-onset diabetes mellitus.

To investigate whether leg exercise accelerates the absorption of exogenous insulin from Its subcutaneous depot in insulin-treated diabetics, and whether the glycemie response to exercise in these patients is related to alterations in the insulin absorption process, we studied nine insulin-dependent diabetics and four normal subjects during rest and exercise. The diabetics received the regular dose of intermediate-acting insulin, reduced by 20 U, and their morning breakfast. One hour after the meal, 20 U regular insulin (Actrapid, labeled with 125I or unlabeled) was injected into the arm or the leg. Exercise (90 ± 10 W) was initiated 35 min later for three consecutive 10-min periods. In controls, no insulin was injected. Plasma glucagon and C-peptide levels were not changed during exercise, but blood ketone bodies and lactate levels increased significantly. Whether the insulin was injected into the moving or resting limb, external counting over the injection site demonstrated no exercise-induced alteration of the disappearance of 125I-radiation during the exercise period, but revealed a small postexercise enhancement of 125I disappearance only after leg injection. Determination of plasma insulin levels in four diabetics with newly insulin-treated diabetes revealed that circulating insulin had increased by 70% 30 min after the subcutaneous administration of regular insulin and had then plateaued for 45 min. Leg exercise had no additional effect on plasma insulin levels during the physical activity. In normals, exercise lowered circulating plasma insulin to a level approximately one-fifth that in diabetics. Regardless of the insulin injection site, there was an identical glycemie response to exercise, i.e., a pronounced fall of glycemia by 15% immediately and by 50% 30 min after the onset of exercise. In normals glucose homeostasis was not disturbed by exercise. This study demonstrates that moderate leg exercise does not necessarily accelerate the absorption of exogenous insulin; however, it can induce an acute and profound fall in glycemia, which presumably is due to the presence of a fixed hyperinsulinemic state in these patients rather than an alteration of the mobilization of insulin from its subcutaneous depot. Although this study investigated only a specific situation, the results indicate the possibility that exercise-induced hypoglycemia in insulin-treated diabetics is not necessarily prevented by changing the insulin injection site to nonmoving parts Of the body.

Glucagon secretion before and during arginine infusions was tested in 11 patients with diabetes associated with haemochromatosis. The results were compared with those obtained in six normal subjects and five patients with haemochromatosis but normal glucose tolerance. The patients with haemochromatosis, regardless of glucose tolerance, exhibited higer level of plasma immunoreactivity for glucagon (antiserum 30-K) suggesting hyperglucagonaemia. However, additional analysis revealed that a considerable amount of this glucagon immunoreactivity was due to cross-reacting material of high molecular weight, the levels of which were significantly higher in patients with idiopathic haemochromatosis. When this was deducted from the total immunoreactivity measured, the resulting values for true glucagon concentrations were similar to those of normal subjects. The data suggest that (1) patients with idiopathic haemochromatosis, whether or not associated with diabetes, exhibit plasma glucagon levels comparable with those of normal subjects; (2) the plasma of the same patients contains significantly more high-molecular-weight substances reacting with glucagon antiserum 30-K than is present in plasma of normal subjects; and (3) 'hyperglucagonaemia' may be erroneously suggested when glucagon is measured with certain antisera reputed to be specific for glucagon.

A number of disorders including maturity-onset (Type II) diabetes, hypertension and hypertriglyceridemia are frequently associated with adult-onset obesity and improve with energy restriction. It is the premise of this brief review that there are patients with these disorders who are not obese according to standard criteria; but who would also respond favorably to energy restriction. It is proposed that these 'metabolically-obese, normal weight' individuals might be characterized by hyperinsulinism and possibly an increase in fat cell size, compared to patients of similar age, height and weight and/or to themselves at an earlier time. It is also proposed that in some of these individuals inactivity and diet composition might be important contributing factors, and that for them, the appropriate therapy would include exercise and altered diet composition.