The effect of insulin on the leg and splanchnic balance of glucose and gluconeogenic substrates after cardiac surgery

The effect of insulin and glucose infusion on the leg and splanchnic balance of glucose and the gluconeogenic substrates lactate, pyruvate, alanine and glycerol was studied in 13 patients directly after cardiac surgery. Insulin was infused continuously at a rate of 1.0 Unit/kg/hr during 1 hour. Sixteen patients served as a control group and received no insulin and glucose infusion. A significant increase in arterial lactate concentration in both the control group (from 1.40 +/- 0.19 to 1.68 +/- 0.24 mmol/l p less than 0.01) and the insulin group (from 1.58 +/- 0.27 to 2.07 +/- 0.22 mmol/l, p less than 0.05) was observed. The arterial pyruvate concentration was significantly increased (from 0.075 +/- 0.019 to 0.105 +/- 0.021 mmol/l, p less than 0.01) and glycerol was significantly decreased (from 0.15 +/- 0.03 to 0.12 +/- 0.03 mmol/l, p less than 0.05) during the insulin and glucose infusion. The alanine concentration was unchanged in both groups. Insulin and glucose infusion was followed by an increased leg uptake of glucose (from 0.15 +/- 0.14 to 1.06 +/- 0.16 mmol/min/100 ml, p less than 0.05), and by a changed splanchnic glucose balance (from -8.2 +/- 2.8 to +4.0 +/- 1.2 mmol/kg/min, p less than 0.01). A net leg release and at the same time a net splanchnic uptake of all gluconeogenic substrates was observed. The insulin and glucose infusion did not significantly change either the splanchnic balance or the leg balance of the gluconeogenic substrates.     

Insulin and high glucose modulation of phosphatase and reductase enzymes in the human erythrocytes: a comparative analysis in normal and diabetic states

The ability of insulin to influence activities of various protein kinases and protein phosphatases, that are thought to mediate insulin action, are limited in patients with insulin resistance. Because numerous responses to insulin are affected, we undertook studies to determine whether protein tyrosine phosphatases (PTPs) activities are altered in patients with diabetes syndrome. In order to evaluate abnormal PTP activities, we done a comparative study using erythrocytes from normal and diabetic patients. We determined the activity of the cytosolic acid PTP in basal and insulin-dependent states. Mean basal PTP activities, were found to be significantly higher in diabetics than in normal subjects (type 1 diabetics: 0.36 +/- 0.01 vs 0.28 +/- 0.01 mmol p-nitrophenolate/h per g hemoglobin (Hb), P < 0.001; type 2 diabetics: 0.35 +/- 0.01 vs 0.28 +/- 0.01 mmol p-nitrophenolate/h per g Hb, P < 0.001). Insulin, at concentrations above physiological levels (1 mIU/ml), inhibited the PTP activities in erythrocytes from normal subjects (-15 +/- 4.1%, P < 0.01). Insulin could also modulate glycolysis, probably as a consequence of receptor tyrosine kinase activation, inducing phosphorylation of protein band 3 and hence the release of glycolytic enzymes. We have previously reported that a reductase enzyme in human erythrocytes is dependent on glycolysis being significantly activated (+28 +/- 3.1%, P < 0.001) by high insulin levels (1 mIU/ml). Mean basal reductase activities were found to be significantly lower in diabetics than in normal subjects (type 1 diabetics: 0.77 +/- 0.03 vs 0.97 +/- 0.02 mmol ferrocyanide/20 min per l cells, P < 0.001; type 2 diabetics: 0.77 +/- 0.04 vs 0.97 +/- 0.02 mmol ferrocyanide/20 min per l cells, P < 0.001), indicating altered erythrocyte metabolism in the diabetic patients. High glucose levels were used to mimic hyperglycemia condition, using erythrocytes from normal subjects. At 30 mM glucose, erythrocytic phosphatase activity was stimulated (+32 +/- 4.2%, P < 0.0001), although no effect was observed on the reductase enzyme at the same glucose levels. Results indicated that diabetic disorders appear to be associated with quantitative alterations of erythrocyte acid phosphatase activity and other enzymes that depend on the glycolytic rate (reductase). The overall data suggest that erythrocyte acid phosphatase may have a role in the modulation of glycolytic rates through the control of insulin receptor phosphorylation.     

Impaired subcutaneous absorption of insulin in 'brittle' diabetics

Twenty-four hour plasma free insulin and blood glucose and intermediary metabolite profiles have been measured in 6 C-peptide deficient 'brittle' diabetic patients, during continuous sc and im insulin infusion. During sc infusion free insulin profiles were erratic and unpredictable. Mean 24 h blood glucose levels were raised at 12.6 +/- 2.1 (SE) mmol/l, and 3-hydroxybutyrate at 0.24 +/- 0.08 mmol/l. Blood lactate (1.88 +/- 0.18 mmol/l) and glycerol (0.084 +/- 0.007) were also elevated. Insulin (im) restored free insulin profiles to the normal pattern as found in 'stable' diabetics on sc infusion, with characteristic post-meal peaks (49 +/- 7, 103 +/- 35, and 95 +/- 34 mU/l) and stable night-time levels. Mean 24 h blood glucose was 6.7 +/- 1.1 mmol/l (P less than 0-.05 compared to sc infusion) and 3-hydroxybutyrate 0.07 +/- 0.02 mmol/l (P less than 0.05). Blood lactate (1.67 +/- 0.08 mmol/l) and glycerol (0.10 +/- 0.02 mmol/l) levels remained abnormal. The ratio of plasma free insulin to insulin dose administered was significantly higher during im infusion. In the 6 'stable' diabetics on sc insulin infusion good blood glucose control (7.1 +/- 0.9 mmol/l) was accompanied by clear post-prandial insulin peaks, and stable nocturnal levels. The results strongly suggest that in one category of 'brittle' diabetics there is defective and erratic sc insulin absorption.     

Clinical significance of altered insulin sensitivity in diabetes mellitus assessed by glucose, insulin, and somatostatin infusion

Insulin sensitivity has been determined in primary nonobese diabetics and subjects with borderline glucose intolerance by a newly devised technique using glucose, insulin, and somatostatin infusion. Insulin sensitivity for glucose utilization was decreased in both adult- and juvenile-onset diabetics. Eight out of 88 diabetics had normal insulin sensitivty and were free from microvascular complications. In lean subjects with borderline glucose intolerance, insulin sensitivity was decreased, although an overlap with normal was noted. All obese subjects with borderline glucose intolerance had reduced insulin sensitivity. An inverse relationship was observed between insulin sensitivity and fasting plasma glucose (FPG), and a significant correlation was observed between FPG and steady state plasma glucose levels (SSPG; r = 0.57; P less than 0.001). Improvement of diabetic control in eight diabetics with sulfonylureas decreased SSPG in all (P less than 0.05), although normalization of SSPG was observed in only one. These results indicate that decreased sensitivity of insulin for peripheral glucose utilization may play an important role in the pathogenesis of diabetes. Elevated FPG levels reflect the presence of decreased insulin sensitivity in diabetes mellitus. Although decreased sensitivity is difficult to normalize, it can be enhanced by improving the diabetic control. An effort to maintain or enhance tissue insulin sensitivity in diabetes mellitus may be more important than attempts to stimulate the deteriorating pancreatic beta-cells to secrete more insulin.     

Insulin action and pharmacokinetics in insulin treated diabetics during the third trimester of pregnancy

Insulin action and pharmacokinetics were compared, using the euglycaemic insulin clamp technique, in seven insulin-treated diabetics during the third trimester of pregnancy and one to three weeks post-partum. At an insulin infusion rate of 1 mU/kg/min, insulin mediated glucose disposal was significantly greater (p less than 0.02) following delivery (1.194 +/- 0.138 mmol/m2/min) than in pregnancy (0.761 +/- 0.072 mmol/m2/min) and the rate of decline in insulin mediated glucose disposal, at the end of the insulin infusion, was significantly greater (p less than 0.02) following delivery (24.78 +/- 4.22 mumol/m2/min2) than in pregnancy (15.17 +/- 2.00 mumol/m2/min2). The metabolic clearance rate, distribution space and pharmacological half-life of insulin were not significantly altered by pregnancy. These findings show that the third trimester of pregnancy is associated with steady state insulin resistance accompanied by a reduced rate of insulin deactivation, but normal insulin pharmacokinetics.     

Chronic undernutrition may accentuate the beta cell dysfunction of type 2 diabetes

Seven undernourished and seven obese, insulin-requiring type 2 diabetic subjects, who were matched for age, sex, and duration of diabetes, were subjected to oral glucose tolerance tests. Although fasting glucose and free insulin levels were similar in both groups, glucose tolerance was markedly worse in the undernourished subjects, with a mean incremental glucose area (+/- SE) of 22.8 +/- 2.3 mmol/l.h vs. 12.4 +/- 1.3 in the obese diabetic subjects (P less than 0.001). The incremental insulin response (area under the curve) to oral glucose in the undernourished group (39.3 +/- 7.9 mU/l.h) was 50% lower than the response in both the obese group (89.2 +/- 19.9, P less than 0.001) and a group of non-diabetic, normal weight-for-height subjects (77.1 +/- 5.7, P less than 0.01). Peak insulin levels were similarly reduced to approximately half the levels seen in the obese and control groups (P less than 0.01). Undernutrition is known to impair both glucose tolerance and insulin secretory reserve by reducing the beta cell number, size, and granulation. It is concluded that chronic undernutrition accentuates beta cell dysfunction in undernourished diabetics, leading to increased glucose intolerance.     

Cholinergic blockade with pirenzepine induces dose-related reduction in glucose and insulin responses to a mixed meal in normal subjects and non-insulin dependent diabetics

OBJECTIVE: The aim of the study was to assess the effects of cholinergic blockade with pirenzepine on glucose and insulin responses to a mixed meal in normal subjects and patients with non-insulin dependent diabetes (NIDDM). Further, to assess in normal subjects the relative importance of nocturnal GH suppression by pirenzepine. DESIGN: Placebo, 100 or 200 mg pirenzepine were given to the normal subjects 1 hour before a standard mixed meal. The effects of placebo or 200 mg pirenzepine at night on nocturnal GH secretion and subsequent breakfast carbohydrate tolerance were also studied. NIDDMs were given placebo or 200 mg pirenzepine before the meal. SUBJECTS: We studied six healthy male volunteers (ages 20-22, body mass indices 20.3-23.3) and ten NIDDMs (eight men, ages 42-74); five obese (BMI 25.5-31.8) and five non-obese (BMI 21.2-24.8). MEASUREMENTS: Serial plasma glucose and insulin concentrations were measured for 3 hours after a standard mixed meal. RESULTS: Acute pretreatment of normal male volunteers with pirenzepine produced a dose-related improvement in carbohydrate tolerance. Peak post-prandial plasma glucose levels were delayed and significantly reduced following 200 mg orally (6.5 +/- 0.1 mmol/l), but not following 100 mg (7.3 +/- 0.3), compared with placebo (7.6 +/- 0.3). Peak insulin levels were similarly delayed and reduced by the 200 mg dose only (36.5 +/- 6.1 mU/l, compared with 49.8 +/- 8.7). Suppression of nocturnal GH by 200 mg pirenzepine at night produced a small reduction in fasting plasma glucose (5.0 +/- 0.1 mmol/l, compared with 5.3 +/- 0.1, P less than 0.02) but did not improve subsequent breakfast carbohydrate tolerance. Peak plasma glucose in NIDDMs was reduced following pirenzepine (12.4 +/- 0.9 mmol/l) compared with placebo (14.3 +/- 1.0, P less than 0.01). This reduction was equally significant in obese and non-obese groups. Peak plasma insulin was also reduced by pirenzepine (22.4 +/- 3.9 mU/l) compared with placebo (42.4 +/- 5.3, P less than 0.01). Insulin suppression was quantitatively greater in obese than in non-obese patients. CONCLUSIONS: Improvement in carbohydrate tolerance after pirenzepine in normal subjects is dose related and largely independent of GH suppression. Cholinergic blockade can also improve meal carbohydrate tolerance with simultaneous reduction in plasma insulin concentrations in non-insulin dependent diabetics, particularly those with obesity.     

Fractional hepatic extraction of insulin in man: is it constant?

The present study was designed to compare insulin extraction by the liver following oral glucose administrations of different size, in order to evaluate insulin removal by the liver in relation to the insulin exposure, and to the amount of ingested glucose. Insulin secretion by the pancreas was estimated by the measurement of peripheral C-peptide levels, and insulin extraction by the liver by the analysis of peripheral C-peptide to insulin ratios and relations. Ten healthy subjects (5 males and 5 females), aged 16 to 66 yr, with normal bw, and without family history of diabetes mellitus were investigated by means of the administration, on alternate days, of 50 and 150 g oral glucose loads. After the 150 g oral glucose load plasma glucose levels were significantly higher than after the 50 g oral glucose administration: glucose incremental areas of 1.45 +/- 0.12 vs. 0.55 +/- 0.04 mmol/l X min, respectively (p less than 0.001). Similarly, insulin concentrations were significantly higher following 150 g than after 50 g glucose ingestion: insulin incremental areas of 0.52 +/- 0.09 vs. 0.20 +/- 0.04 nmol/l X min (p less than 0.001). Also C-peptide levels were higher after 150 vs. 50 g oral glucose load: C-peptide incremental areas of 1.85 +/- 0.41 vs. 0.64 +/- 0.13 nmol/l X min (p less than 0.01). C-peptide to insulin molar ratios were similar during the two glucose challenge, and averaged 5.25 +/- 0.42 vs. 5.08 +/- 0.50 after 50 and 150 g oral glucose loads, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin resistance, but normal basal rates of glucose production in patients with newly diagnosed mild diabetes mellitus

Fasting hyperglycemia in Type II (non-insulin-dependent) diabetes has been suggested to be due to hepatic overproduction of glucose and reduced glucose clearance. We studied 22 patients (10 lean and 12 obese) with newly diagnosed mild diabetes mellitus (fasting plasma glucose less than 15 mmol/l, urine ketone bodies less than 1 mmol/l), and two age- and weight-matched groups of non-diabetic control subjects. Glucose turnover rates and sensitivity to insulin were determined using adjusted primed-continuous [3-3H]glucose infusion and the hyperinsulinemic euglycemic clamp technique. Insulin-stimulated glucose utilization was reduced in both diabetic groups (lean patients: 313 +/- 35 vs 531 +/- 22 mg.m-2.min-1, p less than 0.01; obese patients: 311 +/- 28 vs 453 +/- 26 mg.m-2.min-1, p less than 0.01). Basal plasma glucose concentrations decreased 0.43 +/- 0.05 mmol/l per h (p less than 0.01). Glucose production rates were smaller than glucose utilization rates (lean patients: 87 +/- 3 vs 94 +/- 3 mg.m-2.min-1, p less than 0.01; obese patients: 79 +/- 5 vs 88 +/- 5 mg.m-2.min-1, p less than 0.01), were not correlated to basal glucose or insulin concentrations, and were not different from normal (lean controls: 87 +/- 4 mg.m-2.min-1; obese controls: 80 +/- 5 mg.m-2.min-1). These results suggest that the basal state in the diabetic patients is a compensated condition where glucose turnover rates are maintained near normal despite defects in insulin sensitivity.     

Persistent abnormalities of the metabolism of an oral glucose load in insulin-treated type I diabetics

We have compared disposal of an oral glucose load in 12 normal subjects and 10 c-peptide-negative, type I-diabetic subjects, who were treated with insulin (by overnight intravenous insulin infusion followed by a dose of subcutaneous insulin prior to the oral glucose load) to achieve a blood glucose profile that approximated the glucose intolerance commonly seen in insulin-treated diabetics. We used a combination of the dual-isotope and forearm techniques, together with whole-body indirect calorimetry, to quantify the various determinants of glucose tolerance. The diabetic subjects had impaired glucose tolerance in that, despite similar fasting plasma glucose levels (5.46 +/- 0.17 mmol/L v 5.35 +/- 0.10 mmol/L in the normal subjects), they had a higher peak glucose (14.3 +/- 1.2 mmol/L v 10.0 +/- 0.7 mmol/L P less than .01) and area under the glucose curve (2,483 +/- 197 mmol.min/L v 1,525 +/- 43 mmol.min/L P less than .001). Up to 120 minutes after the oral glucose load, the amount of glucose entering the systemic circulation exceeded that leaving by 14.6 +/- 2.3 g in the diabetics and only by 2.6 +/- 0.5 g in the normal subjects (P less than .001), accounting for the higher plasma glucose peak in the diabetics. Total systemic glucose appearance rates were significantly greater in the diabetics between 60 and 120 minutes, and endogenous glucose production suppressed more slowly in diabetics than in the normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin and glucagon secretion in diabetic and non-diabetic patients with circulating islet cell antibodies

Summary Thirty-nine patients (14 non-diabetics, 8 chemical diabetics, and 17 overt diabetics) with circulating islet cell antibodies (ICA) were studied. Insulin and glucagon secretion after oral (100 g) and intravenous glucose loading (200 mg/kg bolus injection followed by an infusion of 20 mg/min over 60 min) and arginine infusion (25 g over 30 minutes) were evaluated in these patients and in non diabetic and diabetic ICA-negative controls. In the non-diabetic groups with or without ICA, insulin and glucagon responses to glucose were similar. Moreover, in ICA positive patients the response of these hormones to arginine infusion was reduced. Similar alterations in insulin and glucagon secretion were observed in the ICA positive and negative patients with chemical or overt diabetes. In particular, fasting hyperglucagonaemia and glucagon hyperresponse to arginine are associated with a lack of insulin secretion in the patients with overt diabetes. Hormonal differences between diabetics with and without ICA could not be detected.This work was previously presented at the 12th Meeting of the European Association for the Study of Diabetes, Helsinki, September 1976 and published in abstract form in Diabetologia12, 422 (1976)     

Metabolic effects of adrenaline and noradrenaline in man: studies with somatostatin

The metabolic responses to infusion of adrenaline (6 micrograms/min) and of noradrenaline (5 micrograms/min) for 120 minutes have each been studied in five normal males with and without concurrent somatostatin (250 micrograms/h). Adrenaline induced marked and sustained hyperglycaemia (maximal blood glucose at 75 min, 9.0 +/- 0.4 mmol/l) while noradrenaline induced only a mild and transient blood glucose rise. Blood lactate was elevated by adrenaline (2.57 +/- 0.47 mmol/l with adrenaline, 0.62 +/- 0.06 mmol/l with saline at 120 min, p less than 0.02). Pyruvate levels rose proportionately less so that the circulating lactate:pyruvate ratio was increased (16.6 +/- 1.3 with adrenaline, 11.4 +/- 0.9 with saline at 120 min, p less than 0.05). Lactate and pyruvate levels were unaffected by noradrenaline. Both catecholamines increased circulating non-esterified fatty acid (NEFA) and glycerol to peak at 30 min, while maximal 3-hydroxybutyrate concentrations were achieved at 50 min (0.26 +/- 0.07 mmol/l with adrenaline; 0.23 +/- 0.06 mmol/l with noradrenaline; 0.03 +/- 0.01 mol/l with saline, both p less than 0.05). Insulin levels were partially suppressed by noradrenaline, while a small rise in circulating insulin was observed with adrenaline which was also associated with a large rebound rise in insulin secretion on cessation of the infusion. Mild and transient hyperglucagonaemia was observed with adrenaline while stimulation of glucagon secretion was more sustained with noradrenaline. Somatostatin suppressed insulin, glucagon and growth hormone secretion and both magnified and prolonged the hyperglycaemic effect of adrenaline (maximal at 105 min, 11.3 +/- 0.5 mmol/l, p less than 0.01 versus adrenaline alone).(ABSTRACT TRUNCATED AT 250 WORDS)     

Abnormalities in fasting circulating proinsulin concentration in mild gestational diabetes

Fasting plasma proinsulin, insulin and glucose concentrations were measured in ten women with mild gestational diabetes and ten controls matched for race, age (32 +/- 6 vs 31 +/- 6 years), body mass index (28 +/- 8 vs 27 +/- 6) and gestational week (24 +/- 4 vs 25 +/- 4 weeks). There was no significant difference in fasting plasma glucose between these gestational diabetics and their controls (median 4.7, range 3.7-6.0 mmol/l vs 4.5, range 3.4-5.3 mmol/l). The fasting proinsulin levels were significantly higher in the gestational diabetics compared with the controls (median 12.2, range less than 4-14.8 pmol/l vs 5.8, range less than 4-12.8 pmol/l, P less than or equal to 0.02, Wilcoxon Summed Rank Test), while the calculated intact insulin levels (immunoreactive insulin minus proinsulin) were significantly lower (median 14.5, range 6.3-81.8 pmol/l vs 51.6, range 11.7-312 pmol/l, P less than or equal to 0.01). The ratio of proinsulin to calculated intact insulin was significantly higher in the gestational diabetics than the controls (median 0.66, range 0.16-2.04 vs 0.12, range 0.03-0.62), P less than or equal to 0.01). These results demonstrate that gestational diabetics, with normal fasting plasma glucose values, have abnormalities in pancreatic beta-cell secretion, which are likely to be important both in the aetiology of gestational diabetes and non-insulin dependent diabetes.     

Effects of intensive dietary treatment on insulin-stimulated skeletal muscle glycogen synthase activation and insulin secretion in newly presenting type 2 diabetic patients

Ten newly presenting, untreated, Europid Type 2 diabetic patients were studied before and after 8 weeks treatment with intensive diet alone. Nine normal control subjects were also studied. The degree of activation of skeletal muscle glycogen synthase (GS) was used as an intracellular marker of insulin action, prior to and during a 240-min insulin infusion (100 mU kg-1 h-1). Fasting blood glucose decreased from 12.1 +/- 0.9 (+/- SE) to 9.2 +/- 0.8 mmol l-1 (p less than 0.01), but there was no change in fasting insulin concentrations, 9.9 +/- 2.3 vs 9.3 +/- 2.1 mU l-1. Fractional GS activity did not increase in the Type 2 diabetic patients during the insulin infusion either at presentation (change -1.5 +/- 1.9%) or after treatment (change +0.9 +/- 1.8%), and was markedly decreased compared with the control subjects (change +14.5 +/- 2.8%, both p less than 0.001). Glucose requirement during the clamp was decreased in the Type 2 diabetic patients at presentation (2.2 +/- 0.7 vs 7.3 +/- 0.6 mg kg-1 min-1, p less than 0.001), and despite improvement following dietary treatment to 3.3 +/- 0.6 mg kg-1 min-1 (p less than 0.01) remained lower than in the control subjects (p less than 0.001). Fasting plasma non-esterified fatty acid (NEFA) concentrations were elevated at presentation (p less than 0.05), and failed to suppress normally during the insulin infusion. After treatment fasting NEFA concentrations decreased (p less than 0.05) and suppressed normally (p less than 0.05). Insulin secretion was assessed following an intravenous bolus of glucose (0.5 g kg-1) at euglycaemia before and after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Time-dependent effect of hyperglycemia and hyperinsulinemia on oxidative and non-oxidative glucose metabolism in patients with NIDDM.

The present study was undertaken to compare the effect of hyperglycemia and euglycemia during identical hyperinsulinemic conditions on glucose metabolism in NIDDM subjects. Eight NIDDM subjects participated in a 4 h hyperglycemic (12.1 +/- 0.7 mmol/l), hyperinsulinemic (475 +/- 43 pmol/l) and in a 4 h euglycemic (5.5 +/- 0.5 mmol/l), hyperinsulinemic (468 +/- 36 pmol/l) insulin clamp in combination with indirect calorimetry and [3H]-3-glucose. Six non-diabetic subjects were studied during euglycemia (5.1 +/- 0.2 mmol/l) and hyperinsulinemia (474 +/- 35 pmol/l) and served as controls. In NIDDM patients the rate of insulin-stimulated glucose disposal was 57% greater during hyperglycemia compared with euglycemia throughout the 4 h clamp (p less than 0.01). The major part of the increase in glucose metabolism during hyperglycemia was due to an increase in the non-oxidative glucose metabolism (89%). Whereas glucose metabolism could not be normalized during the prolonged euglycemic hyperinsulinemic clamp in NIDDM patients (49.9 +/- 6.8 vs 57.5 +/- 5.4 mumol.(kgLBM)-1.min-1 in controls) the addition of hyperglycemia resulted in complete normalization of the glucose disposal rates (78.3 +/- 5.8 mumol.(kgLBM)-1.min-1). The effect of hyperglycemia was apparent already at 60 min of the clamp. The data thus suggest that glucose metabolism in NIDDM is insulin resistant, but that the defect in insulin-stimulated glucose uptake can be overcome by increasing the glucose concentration.     

Exercise-induced hypoglycaemia and subcutaneous insulin infusion

To assess whether exercise-induced hypoglycaemia could be prevented by interruption of insulin infusion (3 h) we studied diabetic patients treated with continuous subcutaneous insulin infusion (CSII). The studies were performed in 7 insulin-dependent diabetics (aged 31.4 +/- 4.8 (mean +/- SD) years, duration of diabetes 16.9 +/- 5.4 years), after an overnight fast and in the afternoon, 4 h after the last pre-meal bolus injection (exercise and control period). Bicycle exercise (45 min at 60% of maximum oxygen consumption) was started 30 min after the insulin infusion was stopped. During exercise there was a more pronounced decline in blood glucose in the afternoon (2.2 +/- 0.3 mmol/l, mean +/- SEM) than in the morning (1.4 +/- 0.4 mmol/l) (p less than 0.01). This corresponded to higher mean levels of free insulin during exercise in the afternoon (20 +/- 4.5 mU/I vs 12.0 +/- 1.0 mU/l, in the morning). Interruption of insulin delivery for 3 h resulted in a moderate increase of blood glucose, a gradual decrease of free insulin, and a moderate increase in free fatty acids and beta-hydroxybutyrate. During exercise in the afternoon 3 diabetics suffered from symptomatic hypoglycaemia (BG less than 2.8 mmol/l). In contrast with most of the other patients they showed no decline of free insulin during exercise. Thus even after interruption of basal rate insulin infusion moderate postprandial exercise may lead to hypoglycaemia if there is relative hyperinsulinism.     

Significance of plant sterols in diabetes

Plant sterols occur naturally in plants and vegetable oils. Sitosterol and campesterol are markers of cholesterol absorption. The ratio of cholesterol endogenous synthesis to its absorption may be assessed by sitosterol, campesterol and other non-cholesterol sterols (lathosterol and squalen) serum concentration measurements. In 38 Type 2 diabetics (59.9 years, BMI 29.8 kg/m2, HbA1c 7.6%, C-peptid 0.82 nmol/l) and in 40 non-diabetics (37.2 years, BMI 25.4 kg/m2, HbA1c 5.2%, C-peptid 0.85 nmol/l) plant sterols serum concentration were measured: lathosterol (diabetics 10.64, non-diabetics 6.04 mumol/l, p = 0.09), squalen (diabetics 3.42, non-diabetics 1.78 mumol/l, p < 0.01), sitosterol (diabetics 3.91, non-diabetics 3.80 mumol/l, p = 0.60) and campesterol (diabetics 7.91, non-diabetics 8.85 mmol/l, p = 0.09). In non-diabetics squalen positive correlates with C-peptid, lathosterol with triacylglycerols and campesterol with HbA1c. In diabetics correlates diabetes compensation with plant sterols value negative. It seems that plant sterols and probably also cholesterol absorption can be influenced negative by higher value HbA1c.     

Serum alpha 1-protease inhibitor in diabetes mellitus: reduced concentration and impaired activity

We investigated possible alterations in serum alpha 1-protease inhibitor (alpha 1-PI) concentration and activity from insulin-dependent diabetic subjects (IDDs) and in vitro in serum samples containing high glucose concentrations. The in vivo measurements were compared to others taken from normal reference subjects and the in vitro measurements were performed in serum samples containing 0, 10, 20, and 40 mmol/l of glucose. The diabetics had a significantly lower mean alpha 1-PI concentration in their serum than did the reference subjects (1.74 +/- 0.1 g/l vs. 2.1 +/- 0.1 g/l, P less than 0.05), as well as a lower total alpha 1-PI inhibitory activity (201 +/- 0.7 vs. 246.9 +/- 13.5 U/l, P less than 0.02). Addition of glucose to the serum samples in the in vitro study significantly reduced the mean alpha 1-PI concentrations (P less than 0.01 in the case of 10 mmol/l glucose, and P less than 0.001 in the cases of 20 and 40 mmol/l). Added glucose also significantly reduced the mean serum alpha 1-PI activity as determined by the percentage of elastase inhibition in 1, 2, and 3 microliters of reference serum (P less than 0.02 in the case of 10 mmol/l glucose, P less than 0.01 in 20 mmol/l, and P less than 0.001 in 40 mmol/l). Hyperglycaemia thus impaired serum alpha 1-PI concentration and activity both in vivo and in vitro. While the underlying mechanisms and clinical implications of these observations are unknown, the abnormally low alpha 1-PI activity in diabetics may worsen the severity and contribute to the chronicity of their infections.     

A DIRECT ASSAY FOR PROINSULIN IN PLASMA AND ITS APPLICATIONS IN HYPOGLYCAEMIA

A direct radioimmunoassay in unextracted plasma is described. The assay has a sensitivity of 4 pmol/l (2 standard deviation from zero). The proinsulin antiserum was immuno-adsorbed against human C-peptide and insulin coupled to glass beads. Cross-reactivity of the antiserum was assessed and shown to be less than 0.01% with both peptides. In normal healthy fasting subjects the plasma proinsulin level was 6.7 +/- 1.7 pmol/l (n = 17) (mean +/- SD). Fasting proinsulin levels in non-insulin dependent diabetics were significantly elevated compared with non diabetics (14.2 +/- 2 pmol/l (n = 11) vs 6.7 +/- 1.7 (n = 17) P less than 0.005). The insulin/proinsulin ratio was 3.4:1 in the non-insulin dependent diabetic compared with 6:1 in non-diabetics. Samples from 21 insulinoma patients were assayed and mean fasting plasma proinsulin level was 255 pmol/l +/- 479 when the patients were hypoglycaemic. The range in pro-insulin levels was large (30-2300 pmol/l). Mean fasting proinsulin level in three hypoglycaemic subjects due to sulphonylurea overdose was 15.7 +/- 2.3 pmol/l. The molar ratio of proinsulin to insulin was 1:6 in healthy subjects, 1:1 in insulinoma patients and 10:1 in sulphonylurea induced hypoglycaemic patients.     

Decreased insulin binding to erythrocytes in subjects with Klinefelter's syndrome

Insulin binding to specific erythrocyte receptors was investigated in group of 25 subjects with Klinefelter's syndrome (47 XXY genotype) and 14 healthy male volunteers. Insulin binding was significantly decreased in Klinefelter subjects (P less than 0.01 at insulin concentrations of 0.051 and 0.136 mmol/liter); however, their fasting glucose concentration was normal (87 +/- 17), and the glucose disappearance rate was slightly increased (2.3 +/- 0.9; P less than 0.2). These data indicated a compensatory, mechanism involved in the glucose metabolism in Klinefelter's syndrome.