Effect of obesity on circulating intermediary metabolite concentrations in the absence of impaired glucose tolerance.

The published literature on the influence of obesity on intermediary metabolite concentrations does not adequately address the potential confounding effects of the increased prevalence of impaired glucose tolerance in obese subjects. In order to remove this, we studied 109 subjects with proven normal glucose tolerance ranging from underweight to grossly obese (range 15.3-80.9 body mass index). All had blood intermediary metabolites, plasma insulin and C-peptide measured after an overnight fast. Thirty-six (18 from each end of the range of body mass index) received a 3-hour oral glucose tolerance test for metabolites and insulin. Fasting plasma insulin was highly significantly associated with body mass index (r = 0.72; P less than 0.001). Concentrations of lipid intermediaries were better associated with body mass index than with fasting plasma insulin: non-esterified fatty acids (r = 0.36; P less than 0.001), glycerol (r = 0.47; P less than 0.001) and ketone bodies (r = 0.45; P less than 0.001). Fasting concentrations of carbohydrate intermediaries were, however, better correlated with fasting plasma insulin: lactate (r = 0.29; P less than 0.01), pyruvate (r = 0.24; P less than 0.01) and alanine (r = 0.36; P less than 0.001). Glucose concentrations were associated with both to a similar degree (r = 0.33, r = 0.32, respectively; P less than 0.001). After oral glucose, exaggerated rises in plasma insulin and blood glucose were observed in obese subjects but a lesser rise was seen for lactate. Non-esterified fatty acids and ketones, although having higher fasting concentrations in obese subjects, fell to similar concentrations in the two groups after glucose whereas blood glycerol did not fall so far in the obese subjects. The results suggest, even if those subjects with impaired glucose tolerance are excluded, insensitivity to insulin in several aspects of intermediary metabolism in obesity the degree of which may vary in different metabolic pathways or tissues.     

Abnormalities of intermediary metabolism following a gestational diabetic pregnancy

OBJECTIVE--The aim of this study was to compare intermediary metabolism in glucose tolerant women with previous gestational diabetes and control women without a history of gestational diabetes. SUBJECTS--Fifteen women with previous gestational diabetes and 15 controls individually matched for race, age and body mass index were included. Only subjects with normal glucose tolerance were included in this study. METHODS--Plasma glycerol, 3-OH butyrate, non-esterified fatty acids (NEFA), glucose and insulin were measured fasting and following a 75 g oral glucose load. RESULTS--The women with previous gestational diabetes and their matched controls were of similar racial origin, age and body mass index. There was no difference between those with previous gestational diabetes and controls in fasting glycerol, 3-OH butyrate, NEFA, glucose or insulin concentrations. Following the oral glucose load, glycerol, 3-OH butyrate and NEFA concentrations fell in both groups. However, compared with controls at 120 minutes, those with previous gestational diabetes had significantly higher concentrations of glycerol (median 57, range 24-216 vs 27, range 8-89 mumols/l, P less than 0.005) and 3-OH butyrate (9, range 1-18 vs 5, range 2-11 mumols/l, P less than 0.01). NEFA concentrations were similar in the two groups. Despite similar glucose concentrations during the oral glucose tolerance test the insulin response during the first 60 minutes following oral glucose was significantly reduced in the subjects with previous gestational diabetes when compared with controls (insulin area, 0-60 minutes; 2172, range 788-4767 vs 2830, range 996-4784 pmol min/l, P less than 0.05). CONCLUSIONS--Women with a previous history of gestational diabetes, despite having normal glucose tolerance, have defective insulin release with resultant abnormalities of intermediary metabolism.     

Regulation of non-esterified fatty acid and glycerol concentration by insulin in normal individuals and patients with type 2 diabetes.

Plasma glycerol and non-esterified fatty acid (NEFA) concentrations were determined in the basal state and in response to physiological hyperinsulinaemia in 30 non-obese individuals, 15 with Type 2 diabetes and 15 with normal glucose tolerance. Patients with Type 2 diabetes had higher basal concentrations of both glycerol (81 +/- 7 (+/- SE) vs 61 +/- 7 mumol l-1, p less than 0.05) and NEFA (842 +/- 40 vs 630 +/- 46 mumol l-1, p less than 0.002). Plasma NEFA and glycerol concentrations fell in both groups when steady-state plasma insulin concentrations were raised to approximately 450 pmol l-1 by an infusion of exogenous insulin, but plasma concentrations of glycerol (28 +/- 3 vs 13 +/- 3 mumol l-1, p less than 0.002) and NEFA (186 +/- 15 vs 109 +/- 14 mumol l-1, p less than 0.001) were still higher in patients with Type 2 diabetes. Percentage decrease in glycerol from basal levels in response to insulin was significantly less in patients with Type 2 diabetes than in control subjects (64 +/- 3 vs 80 +/- 3%, p less than 0.005); percentage decrease in plasma NEFA concentration was similar in the two groups (78 +/- 3 vs 80 +/- 4%). These results suggest that both plasma glycerol and NEFA concentrations are higher than normal in patients with Type 2 diabetes when measured at the same insulin concentration, both under basal conditions and in response to physiological hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic abnormalities in obese patients with impaired glucose tolerance

It is not clear whether the glucose tolerance test diagnosis of Impaired Glucose Tolerance introduced in the recent revisions of diagnostic criteria is associated with abnormalities of intermediary metabolism other than glucose. Intermediary metabolite concentrations have therefore been studied fasting and in response to oral glucose in 35 patients referred with morbid obesity accompanied by either normal glucose tolerance (18 patients) or Impaired Glucose Tolerance (17 patients). When fasting obese patients with Impaired Glucose Tolerance had significantly higher blood total ketone body concentrations, 0.24 (0.19-0.30) vs 0.14 (0.12-0.16) mmol l-1 (antilog of mean-SE to mean + SE) (p less than 0.05), and lower blood glycerol concentrations, 0.14 +/- 0.01 vs 0.18 +/- 0.01 mmol l-1 (mean +/- SE) (p less than 0.05), than obese patients with normal glucose tolerance. There were no significant differences in fasting insulin, 16 (15-18) vs 14 (12-15) mU l-1, or glucose levels, 5.3 +/- 0.2 vs 5.1 +/- 0.2 mmol l-1. After oral glucose there was an exaggerated rise in glucose, insulin, lactate, and pyruvate in patients with Impaired Glucose Tolerance.     

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)     

Insulin resistance in multiple aspects of intermediary metabolism in myotonic dystrophy

The responses of circulating intermediary metabolites to a low-dose incremental insulin infusion (basal, 0.005, 0.01, and 0.05 U.kg-1.h-1) were examined in eight ambulant subjects with the multisystem disorder, myotonic dystrophy. Eight healthy subjects matched for age, gender, and body mass index served as controls. Oral glucose tolerance (75 g) was normal in all subjects. Basal (postabsorptive) hyperinsulinemia was observed in the subjects with myotonic dystrophy (8.4 +/- 2.0 v 2.3 +/- 0.2 mU/L, P less than .01) with increased basal C-peptide levels. Basal blood glycerol (0.09 +/- 0.02 v 0.05 +/- 0.01 mmol/L, P less than .05), lactate (1.14 +/- 0.12 v 0.77 +/- 0.07 mmol/L, P less than .02), and pyruvate (0.08 +/- 0.01 v 0.05 +/- 0.01 mmol/L, P less than .02) were also elevated in these subjects. During the incremental insulin infusion, circulating insulin (F = 8.2, P less than .02) and C-peptide (F = 5.1, P less than .05) levels were significantly higher in the myotonic subjects. Despite the hyperinsulinemia, circulating concentrations of lactate (F = 9.8, P less than .01), pyruvate (7.8, P less than .02), and glycerol (F = 7.5, P less than .02) were also higher in the subjects with myotonic dystrophy, providing prima facie evidence of insulin resistance in the regulation of these metabolites. During the highest insulin rate, isotopically determined metabolic clearance rate of glucose was significantly lower in the myotonic subjects (3.6 +/- 0.4 v 5.5 +/- 0.7 mL.kg-1.min-1, P less than .05), indicating impaired peripheral glucose metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of non-esterified fatty acids in the deterioration of glucose tolerance in Caucasian subjects: results of the Paris Prospective Study

Summary Although an increased plasma non-esterified fatty acid (NEFA) concentration has been shown to increase insulin resistance (Randle cycle), decrease insulin secretion and increase hepatic gluconeogenesis, the effect of NEFA on the deterioration of glucose tolerance has not been studied prospectively in Caucasian subjects. Therefore, we investigated whether plasma NEFA may be regarded as predictors of deterioration of glucose tolerance in subjects with normal (NGT, n = 3671) or impaired (IGT, n = 418) glucose tolerance who were participants in the Paris Prospective study. The subjects were first examined between 1967 and 1972 and underwent two 75-g oral glucose tolerance tests 2 years apart with measurements of plasma glucose, insulin and NEFA concentrations. Glucose tolerance deteriorated from NGT to IGT or non-insulin-dependent diabetes (NIDDM) in 177 subjects and from IGT to NIDDM in 32 subjects. In multivariate analysis, high fasting plasma NEFA in NGT subjects and high 2-h plasma NEFA and low 2-h plasma insulin concentrations in IGT subjects were significant independent predictors of deterioration along with older age, high fasting and 2-h plasma glucose concentrations and high iliac to thigh ratio. When subjects were divided by tertiles of plasma NEFA concentration at baseline, there was an increase in 2-h glucose concentration with increasing NEFA in the subjects who did not deteriorate, but no effect of plasma NEFA in those who deteriorated. In subjects with IGT who deteriorated compared with those who did not 2-h plasma insulin concentration was lower but there was no evidence that this resulted from an effect of plasma NEFA. Our data suggest that a high plasma NEFA concentration is a risk marker for deterioration of glucose tolerance independent of the insulin resistance or the insulin secretion defect that characterize subjects at risk for NIDDM. [Diabetologia (1997) 40: 1101–1106] Received: 11 March 1997 and in revised form: 20 May 1997     

The metabolic response to the euglycemic insulin clamp in type I diabetes and normal humans

The euglycemic insulin clamp has been utilized extensively to measure in vivo tissue sensitivity to insulin under various circumstances. Insulin sensitivity is determined from the amount of glucose metabolized under steady state conditions. To assess the effect of abnormalities in other insulin responsive metabolic pathways on glucose metabolism and thus insulin sensitivity as measured by the glucose clamp, the concentration of lactate, pyruvate, 3-hydroxybutyrate, glycerol, alanine, and free fatty acids were measured at baseline and during a two-hour euglycemic clamp in 13 nonobese subjects with type I diabetes. The observed responses were compared to 11 normal controls. Insulin sensitivity as measured by M (glucose metabolized), MCRg (metabolic clearance of glucose), and M/I ratio (glucose metabolized per unit insulin) were all significantly decreased in the diabetic subjects (P less than 0.005). Free fatty acids (FFA) and 3-hydroxybutyrate were significantly elevated at baseline in the diabetic subjects (P less than 0.05) and decreased significantly at 60 and 120 minutes in both groups. Baseline blood pyruvate and lactate concentrations were similar in the control and diabetic subjects. Pyruvate increased significantly at 60 minutes in both groups (P less than 0.05) and returned to baseline in the control subjects but remained elevated at 120 minutes in the diabetic subjects (P less than 0.001). Lactate increased similarly in both groups and remained elevated at 60 and 120 minutes. In summary, insulin sensitivity as assessed by the euglycemic insulin clamp is decreased in type I diabetes. However, specific differences in the concentration of several other metabolites both at baseline and in response to hyperinsulinemia were also identified in the diabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

USE OF COMBINED ORAL CONTRACEPTIVE PREPARATIONS ALTERS THE INSULIN SENSITIVITY OF FATTY ACID AND KETONE METABOLISM

Eight women taking low-dose-oestrogen combined oral contraceptive preparations were compared to eight women in the luteal phase of the menstrual cycle during hourly incremental insulin infusions of 0 (basal), 0.005, 0.01 and 0.05 U/kg/h short-acting insulin. Dose-response relationships between insulin and intermediary metabolites were sought by analysis of variance applied to regression. For insulin (log) and glucose the slope of the relationship was significantly shallower in the oral contraceptive group. For insulin (log) and non-esterified fatty acids the slopes of the regression lines were not different between groups but lines were significantly displaced. For insulin (log) and total ketone bodies (log) slopes of the regression lines were not different but significant displacement was observed. At identical insulin concentrations women taking an oral contraceptive had higher non-esterified fatty acids (NEFA) (difference between groups +0.15 mmol/l, P less than 0.001) and total ketone bodies (log: -0.26 mmol/l, P less than 0.001). The potency of insulin action in oral contraceptive users versus the luteal group was 0.47 (P less than 0.01) for NEFA and 0.38 (P less than 0.001) for total ketone bodies. The results demonstrate, for the first time, in-vivo insulin resistance of NEFA and ketone bodies' metabolism induced by oral contraceptive use.     

Metabolic and hormonal effects of tacrolimus (FK506) or cyclosporin immunosuppression following renal transplantation

Twelve renal transplant recipients randomised to receive immunosuppression with either tacrolimus (FK506) or cyclosporin underwent oral glucose tolerance tests (OGTT) a median of 8 months (range 7-9) after transplantation. Six healthy subjects acted as controls. Compared with the controls, both transplant groups had significantly elevated fasting (p < 0.05 for both groups) and postprandial (p < 0.001 for tacrolimus and p < 0.05 for cyclosporin) blood glucose concentrations. Fasting hyperinsulinaemia was observed in both transplant groups (p < 0.05) relative to the control subjects. Glucose-stimulated plasma immunoreactive insulin concentrations in the tacrolimus-treatment group were significantly higher than in the cyclosporin group (p < 0.05) and the controls (p < 0.001). Postprandial blood alanine concentrations were also significantly elevated in the tacrolimus group compared with both the controls (p < 0.001) and cyclosporin-treated patients (p < 0.001). The raised insulin concentrations with normal or increased blood glucose concentrations after renal transplantation suggests that insulin resistance was more marked in patients receiving tacrolimus-based immunosuppression.     

Metabolic effects of cortisol in man--studies with somatostatin

The metabolic effects of chronic hypercortisolaemia were studied by administration of tetracosactrin-depot, 1 mg I.M. daily for 36-60 hr to normal subjects. Partial insulin and glucagon deficiency were induced at the end of the period by infusion of somatostatin, 100 micrograms/h for 210 min. Tetracosactrin alone induced a three fold rise in basal serum cortisol levels and fasting blood glucose concentration rose from 5.2 +/- 0.2 to 7.2 +/- 0.2 mmole/l (p less than 0.01) with a rise in fasting serum insulin from 5.2 +/- 1.2 to 13.1 +/- 1.9 mU/l (p less than 0.02). Concentrations of the gluconeogenic precursors lactate, pyruvate and alanine were also raised, but non-esterified fatty acid, glycerol and ketone body levels were unchanged. Somatostatin infusion caused a 30%-50% decrease in serum insulin and a 20%-60% decrease in plasma glucagon concentrations both before and after tetracosactrin administration. A similar rise in blood glucose concentration, relative to the saline control, occurred over the period of somatostatin infusion both with and without elevated cortisol levels. However, prior tetracosactrin administration caused a 100% greater rise in blood ketone body concentrations during infusion of somatostatin than was seen in the euadrenal state, despite similar plasma NEFA concentrations. Hypercortisolaemia causes hyperglycaemia and elevated gluconeogenic precursor concentrations but the associated rise in serum insulin concentrations limits lipolysis and ketosis. In insulin deficiency, a ketotic effort of glucocorticoid excess is evident which may be independent of lipolysis and occurs despite concurrent glucagon deficiency. These catabolic actions of cortisol are likely to be of major importance in the metabolic response to stress.     

Assessment of therapy in gestational diabetes by substrate and hormone responses to a standardized test meal

Postprandial substrate and hormone responses to a standard mixed meal (400 kcal) was determined at two occasions, A and B, in 11 women with gestational diabetes (GDMs) and 11 normoglycaemic controls, matched for age, body mass index, and gestational age. Levels of circulating glucose, non-esterified fatty acids (NEFA), glycerol, 3-hydroxybutyrate (3-HBA), individual amino acids, insulin, and C-peptide were analysed. A was performed when GDMs were considered inadequately controlled with diet alone, B later during gestation following initiation of insulin therapy because of hyperglycaemia. Fasting glucose, glycerol, total and individual amino acids (alanine, valine, isoleucine, leucine), insulin, and C-peptide were not different from normal during A and B, neither were postprandial amino acid levels. During test A, GDMs had elevated fasting and postprandial 3-HBA (p < 0.001), greater postprandial rise of glucose (p < 0.001), elevated NEFA (p < 0.05), but normal and parallel decreases of NEFA and glycerol. Insulin and C-peptide responses were delayed and prolonged. During B, GDMs had higher glucose response (p < 0.005), higher fasting 3-HBA (p < 0.02) but similar and parallel decreases of NEFA, glycerol, and 3-HBA as controls. The C-peptide response was not significantly different from normal; insulin response was higher (p < 0.05). In conclusion, the relative insulin deficiency characterizing GDMs, also when treated with insulin, is associated with selected defects in insulin action; mainly affecting glucoregulation, whereas suppression of lipolysis and proteolysis remain normal. © 1997 John Wiley & Sons, Ltd.     

The effect of metformin on glycaemic control, intermediary metabolism and blood pressure in non-insulin-dependent diabetes mellitus

Fourteen non-insulin-dependent diabetics (9 female, 5 male), aged 46 to 64 years, uncontrolled by diet (fasting plasma glucose greater than or equal to 8 mmol/l), were treated with metformin, 1-3 g daily, and followed prospectively at 1 week, then at 2-weekly intervals for 6 months. The fasting plasma glucose fell significantly (p less than 0.01) after 1 week of therapy and HbA1 showed a significant reduction, 13.4 +/- 2.5% (mean +/- SD) to 10.7 +/- 1.8% (normal range 5.1-9.3%) at 8 weeks (p less than 0.001). There was no significant change in body weight, plasma insulin, serum cholesterol or triglycerides, blood lactate, pyruvate, glycerol, alanine, 3-hydroxybutyrate or acetoacetate concentration. Systolic, diastolic, and mean arterial blood pressures, along with resting heart rate remained unchanged. This study shows that metformin effectively lowers plasma glucose without hyperinsulinism or significant rise in fasting blood lactate and other gluconeogenic precursors.     

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 sensitivity in non-diabetic relatives of patients with non-insulin-dependent diabetes from two ethnic groups

OBJECTIVE Non-insulin-dependent diabetes is a heterogeneous disorder, the basis of which may differ in different ethnic groups. In order to investigate early metabolic abnormalities occurring during the development of the condition we assessed insulin secretion and insulin action in subjects predisposed to the later development of non-insulin-dependent diabetes from two different ethnic groups. DESIGN Subjects were studied on two separate occasions by an oral glucose tolerance test and a short insulin tolerance test. PATIENTS Twenty-four glucose-tolerant first-degree relatives of patients with non-insulin-dependent diabetes (12 of European and 12 of Asian origin) were compared with 24 ethnically matched control subjects with no family history of diabetes. MEASUREMENTS Insulin, proinsulin, glucose and intermediary metabolites were measured during a 75-g oral glucose tolerance test. Insulin sensitivity was assessed using a 15-minute insulin tolerance test (0.05 units/kg). RESULTS Asian relatives compared to Asian controls had significantly higher fasting levels of immunoreactive insulin (83 ± 17 vs 40 ± 6 pmol/l, P < 0 05), which were not due to increased proinsulin. Blood glycerol concentrations were elevated (83 ± 9 vs 51 ± 4 μmol/l, P < 0.005), but fasting glucose and non-esterified fatty acid (NEFA) concentrations were similar. Relatives of European origin did not differ from their European controls in any of these measurements. The glucose response to oral glucose was similar in relatives and controls, irrespective of ethnic group. The insulin responses were non-significantly greater in relatives from both ethnic groups. Proinsulin levels were not significantly different. Asian relatives had higher circulating glycerol and NEFA levels after oral glucose than Asian controls, but these differences were not observed in the European group. Insulin sensitivity was reduced in the Asian relatives compared to their controls (183 ± 7 vs 139 ± 12μmol/l/min, P < 0.01) but there was no difference in insulin sensitivity between the European relatives and European controls (167 ± 11 vs 160 ± 11 μmol/l/min). CONCLUSIONS First-degree relatives of non-insulin-dependent diabetic patients of Asian, but not of European, origin are insulin insensitive in terms of both glucose metabolism and lipolysis, and have true hyperinsulinaemia. This suggests that insulin insensitivity may be an early abnormality in the development of non-insulin-dependent diabetes in the Asian population.     

Determinants of mild fasting hypertriglyceridaemia in non-insulin-dependent diabetes

Factors contributing to fasting hypertriglyceridaemia were studied in 20 patients with non-insulin-dependent diabetes--nine with normal triglyceride concentrations [fasting triglyceride 0.94 (range 0.58-1.23) mmol l-1] and eleven with mild fasting hypertriglyceridaemia [fasting triglyceride 2.4 (1.82-4.0) mmol l-1]. The patients with hypertriglyceridaemia were more obese [body mass index 29.0 (24.6-33.8) vs. 25.7 (21.9-30.1) kg m-2, P less than 0.05] and demonstrated impaired glucose disposal in response to exogenous insulin at isoglycaemia [insulin sensitivity index, SIp 0.7 (0.27-2.5) vs. 2.4 (0.62-5.1) ml m-2 min per mU l-1, P less than 0.001]. Basal non-esterified fatty acid (NEFA) and glycerol concentrations were higher and were suppressed to a lesser extent during isoglycaemic hyperinsulinaemia. Fasting glucose and apolipoprotein B concentrations were higher in the hypertriglyceridaemic patients, but lipoprotein lipase activities were similar in the two groups. When the effect of obesity was removed (by weight-matching six normotriglyceridaemic with seven hypertriglyceridaemic patients) basal NEFA and glycerol concentrations and the suppression of NEFA in response to insulin remained significantly different between the two groups. We propose that defects in both the glucoregulatory and antilipolytic actions of insulin contribute to mild fasting hypertriglyceridaemia in NIDDM, and that these defects cannot be attributed solely to obesity. These disorders of insulin action may also have important implications for the postprandial metabolism of triglyceride-rich lipoproteins and hence atherogenesis.     

The effect of an eucaloric high carbohydrate diet on circulating levels of glucose, fructose and non-esterified fatty acids in patients with cirrhosis.

Twelve cirrhotic patients and six controls were fed an eucaloric high carbohydrate (CHO) diet for 3 days. Fasting serum triglyceride (TG), non-esterified fatty acids (NEFA), glucose, insulin and glycerol were estimated daily. On the 3rd day of the study we measured NEFA, glucose, insulin, and fructose every 45 min from 07:45 h until 19:45 h, and then every 4 h until 07:45 h the next day. The patients were divided into two groups of six on the basis of plasma lecithin-cholesterol acyltransferase (LCAT) activity: group A cirrhotics (with good liver function--LCAT activity: 40.6-65.7 nmol.ml-1.h-1; mean 48.5), and group B (poor liver function--LCAT: 23.7-32.3; mean 27.4). On the high CHO diet there was an increase in the fasting serum TG with a peak after 2 or 3 days. The increase in serum TG in controls was greater (p less than 0.01) than in either group of cirrhotics. In the controls and in group A most of the extra TG was carried in VLDL; in group B only 39% of the TG increment was found in VLDL. Fasting NEFA fell with 3 days of CHO feeding in the control group (p less than 0.01); they were unchanged in group A, and rose in group B to a significantly higher level than in controls (p less than 0.01). During day 3 when a high CHO diet was fed plasma NEFA levels fell in cirrhotics, and for most of the day the mean NEFA concentration in group B patients was significantly (p less than 0.05) lower than in normals. On day 3 glucose and fructose levels rose after each meal--much more in cirrhotics than in controls (and more in group B than in group A), and for most of the day they were significantly higher in group B patients as compared to the controls (glucose p less than 0.01, fructose p less than 0.001). Our results supported the hypothesis that plasma NEFA would be lower following high CHO meals in cirrhotics than in controls. This suggests that a high NEFA utilisation, which occurs in fasting cirrhotics, is not present throughout the day. Following a CHO meal, we suggest that tissues derive energy directly from the dietary sugars which are present in high concentration during the period of absorption and that this reduces the post prandial requirement for NEFA.     

The Relationship Between Obesity,Plasma Immunoreactive Insulin Concentration and Blood Pressure in Newly Diagnosed Indian Type 2 Diabetic Patients

The association of blood pressure with clinical and biochemical measures was studied in 185 newly diagnosed Type 2 diabetic patients, 74 impaired-glucose-tolerant (IGT) and 128 non-diabetic control subjects. Hyperglycaemic subjects were older than control subjects (controls 40 (24–59) years, IGT 48 (29–64) years, diabetic 43 (29–60) years, median (5th-95th centile) both p < 0.05). They were also more obese (body mass index (BMI) controls 23.5 kg m^?2 (17.2–29.9), IGT 26.0 kg m^?2 (19.8–33.9), diabetic 24.2 kg m^?2 (19.3–32.2)) and with a greater waist-hip ratio (controls 0.83 (0.70–0.98), IGT 0.88 (0.75–0.98), diabetic 0.89 (0.75–1.00)). Blood pressure was significantly higher in both IGT (systolic 127mmHg (108–162), diastolic 80 mmHg (66–99)) and diabetic patients (systolic 130 mmHg (104–160), diastolic 84 mmHg (66–102)) compared to non-diabetic controls (systolic 120 mmHg (100–151), diastolic 80 mmHg (60–94)). Univariate analysis showed that in diabetic patients systolic blood pressure was related to age (r = 0.17, p < 0.05), BMI (r= 0.23, p < 0.01) and plasma immunoreactive insulin (fasting and post glucose, r= ? 0.25, p<0.01) but not to C-peptide concentrations; diastolic blood pressure to BMI (r= 0.35, p < 0.001), waist-hip ratio (r = 0.23, p < 0.01) and plasma immunoreactive insulin (fasting r= 0.30, p < 0.001, post glucose r = ? 0.20, p < 0.05) but not to C-peptide concentrations. Multivariate analysis revealed that systolic blood pressure in diabetic patients was related to BMI (p < 0.01) and fasting immunoreactive insulin (p < 0.05) while diastolic blood pressure was related to BMI (p < 0.001) and waist-hip ratio (p < 0.01). Thus, blood pressure is associated with obesity even in our relatively non-obese population and it is also associated with plasma immunoreactive insulin concentrations. The mechanism of these associations remains to be established.     

HYPERINSULINAEMIA IN HYPERPROLACTINAEMIC WOMEN

The metabolic sequelae of hyperprolactinaemia were studied over a 12 h period of normal meals and activity in nine young female hyperprolactinaemic subjects and fourteen matched controls. In the patients, fasting blood glucose and serum insulin concentrations were normal, as was the blood glucose response to meals; the insulin rise with meals was, however, exaggerated and hyperinsulinaemia persisted throughout the day (mean ± SEM 12 h serum insulin, 26 ± 8 vs. 16 ± 9 mu/l, P < 0.01). Blood lactate, pyruvate and alanine response to meals was also increased. Blood glycerol (mean 12 h blood glycerol 0.06 ± 0.01 vs. 0.09 ± 0.01 mmol/l, P < 0.01) and blood 3-hydroxybutyrate (mean 12 h blood 3-hydroxybutyrate 0.03 ± 0.01 vs. 0.05 ± 0.01 mmol/l, P < 0.05) concentrations were lower in hyperprolactinaemic subjects. There was a strong negative correlation between mean insulin and mean 3-hydroxybutyrate levels in the afternoon period (rs = -0.92, P < 0.01). Excess circulating prolactin in young females is associated with normoglycaemic hyperinsulinaemia. The changes in blood metabolite levels observed are probably secondary to the increased insulin concentrations.     

Glucose turnover and recycling in diabetes secondary to total pancreatectomy: effect of glucagon infusion

This study was designed to evaluate whether chronic deficiency of pancreatic glucagon in patients with diabetes secondary to total pancreatectomy (PX) is responsible for the commonly observed increase in blood concentrations of gluconeogenic precursors (alanine, lactate, and pyruvate). Seven PX patients were studied on two different occasions: 1) after an overnight insulin infusion (0.15 mU/kg.min) and 2) after an overnight insulin/glucagon infusion (2 ng/kg.min). Five type 1 diabetic individuals were also studied after a similar overnight insulin infusion. In the morning of each study day, [6-3H]glucose and [1-14C]glucose were rapidly injected for determination of total glucose turnover rate [( 6-3H]glucose) and glucose recycling (difference between [6-3H]glucose and [1-14C]glucose turnover rate). Basal concentrations of hormones, glucose, and intermediary metabolites were measured. After overnight insulin infusion, plasma glucose concentration (3.8 +/- 0.4 vs. 6.8 +/- 1.4 mmol/L), turnover rate (8.4 +/- 1.0 vs. 13.7 +/- 1.9 mumol/kg.min), and percent glucose recycling (5.6 +/- 3.9% vs. 19.0 +/- 3.8%) were significantly lower in PX patients than in type 1 diabetic individuals (P less than 0.05-0.01). On the contrary, blood alanine (459 +/- 93 vs. 263 +/- 28 mumol/L), lactate (1157 +/- 109 vs. 818 +/- 116 mumol/L), and pyruvate (71 +/- 8 vs. 42 +/- 3 mumol/L) were significantly higher than those values in type 1 diabetic patients (P less than 0.05-0.01). Insulin/glucagon infusion increased plasma glucose concentration (8.7 +/- 1.5 mmol/L), total turnover (18.1 +/- 1.7 mumol/kg.min), and percent recycling (20.4 +/- 6.6%) to values similar to those in type 1 diabetic subjects. The change in glucose metabolism was associated with a significant drop in blood concentrations of alanine (179 +/- 24 mumol/L), lactate (611 +/- 25 mumol/L), and pyruvate (30 +/- 3 mumol/L; all P less than 0.05-0.01 vs. insulin infusion alone). In PX patients, the glucose turnover rate was inversely correlated with blood concentrations of both alanine (r = 0.67) and lactate (r = 0.71; P less than 0.01). In conclusion, chronic deficiency of pancreatic glucagon in PX patients 1) is associated with a decreased rate of glucose turnover, 2) causes a marked impairment in glucose recycling (an index of the activity of hepatic gluconeogenesis), and 3) increases blood concentrations of alanine, lactate, and pyruvate. All abnormalities are reversed by glucagon.