Normal proinsulin processing despite beta-cell dysfunction in persistent hyperinsulinaemic hypoglycaemia of infancy (nesidioblastosis)

Summary Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a genetic disorder which causes severe hypoglycaemia in the neonate. The beta cells fail to respond to changes in blood glucose levels in all the stages of the disease, which often ends with NIDDM. Fasting insulin, intact proinsulin and des 31,32 split proinsulin levels were measured in PHHI patients with active disease, patients after partial pancreatectomy, and those in clinical remission. All but one of the pancreatectomized patients developed diabetes and were hyperglycaemic on evaluation. Fasting insulin was comparable in pancreatectomized and medically treated patients. Des 31,32 split proinsulin levels were much higher in pancreatectomized compared to non-pancreatectomized patients (10.7 ± 2.5 vs 3.4 ± 0.8 pmol/l, p = 0.001) and age-matched control subjects (3.8 ± 1.4 pmol/l, p = 0.018). Also the ratio of des 31,32 split proinsulin to total insulin plus proinsulin-like peptides was higher in pancreatectomized patients (18.7 ± 2.8 vs 7.2 ± 0.8 % in non-pancreatectomized patients, p = 0.001, and 6.8 ± 2.1 % in normal control subjects, p = 0.004). Furthermore, des 31,32 split proinsulin was the dominating species of proinsulin-like molecules in the pancreatectomized patients (62.7 ± 1.6 % vs 45.5 ± 3.8 %, and 49.0 ± 3.2 % in non-pancreatectomized patients and control subjects, respectively, p = 0.001 and p = 0.0002). Intact proinsulin levels, and the proinsulin percentage, tended to be higher in pancreatectomized patients; however, the differences did not reach statistical significance. All parameters were similar in non-pancreatectomized patients and age-matched control subjects. Subgroup analysis showed comparable proinsulin-like peptide levels in patients with active disease and those in apparent clinical remission. Fasting levels of insulin and proinsulin-like peptides were also measured in a larger group of healthy children and young adults. Insulin and des 31,32 split proinsulin increased with age, the differences being most prominent when the young age group (0–8 years) was compared to the older groups (8–16 and > 16 years). The fasting levels of plasma insulin were correlated with those of intact proinsulin and des 31,32 split proinsulin (r = 0.82 and 0.81, respectively). Fasting insulin, intact proinsulin and des 31,32 split proinsulin were correlated with BMI (r = 0.55, 0.56 and 0.53, respectively). In summary, relative hyperproinsulinaemia was noted only in PHHI patients with increased secretory demand following pancreatectomy, but not in patients with active disease or those in spontaneous clinical remission. These findings suggest that abnormal proinsulin processing is not an intrinsic feature of PHHI despite the severe beta-cell dysfunction. [Diabetologia (1996) 39: 1338–1344] Received: 28 February 1996 and in revised form: 23 May 1996     

Immunoradiometric assay of insulin,intact proinsulin and 32–33 split proinsulin and radioimmunoassay of insulin in diet-treated Type 2 (non-insulin-dependent) diabetic subjects

Summary Plasma insulin, intact proinsulin and 32–33 split proinsulin measured by specific immunoradiometric assays and insulin and C-peptide measured by radioimmunoassay were measured during a constant infusion of glucose test in ten diet-treated subjects with a history of Type 2 (non-insulin-dependent) diabetes (termed diabetic subjects), mean fasting plasma glucose 6.0 ± 1.0 mmol/l (mean ± SD), and 12 non-diabetic control subjects. Immunoreactive insulin concentrations measured by radioimmunoassay were 33 higher than insulin and 16 % higher than the sum of insulin and its precursors by immunoradiometric assay. The diabetic and non-diabetic subjects had similar fasting concentrations of insulin, intact proinsulin and 32–33 split proinsulin. The ratio of fasting intact proinsulin to total insulin was greater in the diabetic than the non-diabetic group 12.0 % (6.8–21.0 %, 1 SD range) and 6.3 % (4.0–9.8 %), respectively,p < 0.01), though the groups overlapped substantially. After glucose infusion, diabetic and non-diabetic subjects had similar intact proinsulin concentrations (geometric mean 4.9 and 5.2 pmol/l, respectively), but the diabetic group had impaired insulin secretion by immunoradiometric assay (geometric means 55 and 101 pmol/1,p < 0.05) or by radioimmunoassay C-peptide (geometric means 935 and 1410 pmol/1,p < 0.05), though not by radioimmunoassay insulin (87 and 144 pmol/1,p = 0.12), respectively. Individual immunoradiometric assay insulin responses to glucose expressed in terms of obesity were subnormal in nine of ten diabetic subjects. Radioimmunoassay insulin and C-peptide gave less complete discrimination ( subnormal responses in six of ten and eight of ten, respectively). Thus, raised proinsulin and proinsulin:total insulin ratio are not necessarily a feature of mild diet-treated Type 2 diabetic patients with subnormal insulin responses to glucose.     

Disproportionate elevation of immunoreactive proinsulin in Type 2 (non-insulin-dependent) diabetes mellitus and in experimental insulin resistance

Summary In this study, we found that the ratio of proinsulin to total immunoreactive insulin was much higher in 22 patients with Type 2 (non-insulin-dependent) diabetes mellitus than in 28 non-diabetic control subjects of similar age and adiposity (32±3 vs 15±1%, p<0.001). In addition, the arginine-induced acute proinsulin response to total immunoreactive insulin response ratio was greater in diabetic patients (n=10) than in control subjects (n=9) (8±2 vs 2±0.5%, p=0.009), suggesting that increased islet secretion per se accounted for the increased ratio of proinsulin to immunoreactive insulin. One explanation for these findings is that increased demand for insulin in the presence of islet dysfunction leads to a greater proportion of proinsulin secreted from the B cell. We tested this hypothesis by comparing proinsulin secretion before and during dexamethasone-induced insulin resistance in diabetic patients and control subjects. Dexamethasone treatment (6 mg/day for 3 days) raised the proinsulin to immunoreactive insulin ratio in control subjects from 13±2 to 21±2% (p<0.0001) and in diabetic patients from 29±5 to 52±7% (p<0.001). Dexamethasone also raised the ratio of the acute proinsulin response to the acute immunoreactive insulin response in control subjects from 2±0.5 to 5±2% (p=0.01) and in diabetic patients from 8±2 to 14±4% (p=NS), suggesting that the dexamethasone-induced increment in the basal ratio of proinsulin to immunoreactive insulin was also due to increased secretion. We conclude that: (1) The basal proinsulin to immunoreactive insulin ratio is increased in obese Type 2 diabetic patients. (2) An increase in tissue demand for insulin leads to a rise in the proinsulin to immunoreactive insulin ratio, which is exaggerated in Type 2 diabetic patients. (3) The increased proinsulin to immunoreactive insulin ratio in these diabetic patients in the basal state and in diabetic patients and control subjects during experimental insulin resistance is probably due to increased B-cell secretion of proinsulin.     

Hypoglycemic potency and metabolic clearance rate of intravenously administered human proinsulin and metabolites

Since circulating proinsulin has been suggested to be important in the pathogenesis of noninsulin-dependent diabetes, and biosynthetic human proinsulin (HPI) may have a therapeutic role in patients with diabetes mellitus, the biological activity of proinsulin metabolites is of potential significance. Moreover, recent studies have suggested that the majority of circulating proinsulin immunoreactivity consists of metabolites. We, therefore, compared the blood glucose-lowering ability and MCR of the two proinsulin metabolites des-(31,32)HPI and des-(64,65)HPI with intact HPI in seven anesthetized dogs after an overnight fast. Intravenous bolus injections of 12.5 micrograms HPI/kg BW and equimolar amounts of des-(31,32)HPI and des-(64,65)HPI were given on three separate occasions. In addition to blood glucose, des-(31,33)HPI, des-(64,65)HPI, and HPI were measured using an insulin RIA and peptide-specific standard curves. Kinetic parameters were derived by fitting two exponentials to the respective decay curves. The MCR of HPI (3.3 +/- 0.1 ml/kg.min) was significantly lower (P less than 0.05) than that of des-(64,65)HPI (6.4 +/- 0.6 ml/kg.min), but was not significantly different from that of des-(31,32)HPI (3.8 +/- 0.4 ml/kg.min). The MCR of biosynthetic insulin (17.2 +/- 1.8 ml/kg.min), as measured in three of the dogs, was higher than that of HPI or the two metabolites. The blood glucose-lowering ability (defined as nadir glucose/fasting glucose, expressed as a percentage) of des-(64,65)HPI (49.3 +/- 5.0%) was significantly greater (P less than 0.05) than that of intact HPI (87 +/- 2.2%), and the glucose-lowering ability of des-(31,32)HPI (75.2 +/- 3.8%) was intermediate. In conclusion, HPI metabolites are more biologically active than intact HPI. The extent of in vivo conversion of proinsulin to metabolites may enhance the biological activity of proinsulin and, thus, have physiological, pathophysiological, and therapeutic significance.     

Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects — evidence against a modulating role for insulin

Summary Elevated concentrations of proinsulin-like molecules, other than insulin, may be associated with abnormalities of cardiovascular risk factors, promoting atherogenesis and thrombosis. Using specific assays we examined the relationship of levels of insulin, intact proinsulin and des-31,32 proinsulin to blood pressure, lipids, fibrinogen, factor VII and albumin excretion rate in 270 europids with normal glucose tolerance. After correcting for age and body mass index, fasting and 2-h insulin concentrations were significantly associated with those of total and LDL-cholesterol (r=0.18–0.22), HDL-cholesterol (both r=–0.20) and triglycerides (r=0.21 and 0.18), but not with blood pressure. Concentrations of intact and des-31,32 proinsulin showed significant associations with those of total and LDL-cholesterol (r=0.20–0.23), HDL-cholesterol (r=–0.31 and –0.32) and triglycerides (r=0.22 and 0.26). Fasting insulin and intact proinsulin concentrations were significantly associated with fibrinogen (r=0.15 and 0.18). Concentrations of proinsulin-like molecules comprised less than 10% of all insulin-like molecules, and so were calculated not to influence previously described relationships between insulin concentrations and cardiovascular risk factors measured using non-specific assays. In multiple regression analyses des-31,32 proinsulin concentration was more strongly associated with those of HDL-cholesterol (negatively), LDL-cholesterol and triglycerides than fasting insulin concentrations, while intact proinsulin replaced insulin concentrations in their relationships with fibrinogen. Our results show correlations between dyslipidaemia and proinsulin-like molecules at concentrations at which biological, insulin-like, activity appears unlikely. We also show relationships between LDL-cholesterol and fibrinogen and the proinsulin-like molecules. These results suggest that a causal relationship mediated by hyperinsulinaemia and insulin resistance is unlikely.Abbreviations PAI-1 Plasminogen activator inhibitor-1 - PI proinsulin - CV coefficient of variation     

Azygos venous blood flow while fasting, postprandially, and after endoscopic variceal ligation, measured by magnetic resonance imaging

Using cine phase-contrast magnetic resonance (MR) imaging, we measured fasting and postprandial azygos blood flow in 15 cirrhotic patients with portal hypertension and 11 healthy controls. In 10 of the cirrhotics, measurements were made before and after prophylactic endoscopic variceal ligation therapy (EVL). Flow volume was measured in the azygos vein at the level of the midthoracic vertebra. Azygos blood flow was measured under basal fasting conditions and 30–40 min after ingestion of a 500 Kcal meal. Fasting azygos blood flow was 139 ± 43 ml/min in controls vs 519 ± 249 ml/min in cirrhotics (P < 0.01). Eating significantly increased azygos blood flow, by 38% in controls (P < 0.02) and by 27% in cirrhotics (P < 0.02), compared with fasting conditions. EVL markedly decreased azygos blood flow, by 25% compared with pre-EVL (P < 0.03). The cine phase-contrast MR velocity mapping method measured flow volume in the azygos veins. Azygos blood flow was markedly greater in the cirrhotics than in the controls. In the cirrhotics and controls, blood flow volume increased after eating. Azygos blood flow was significantly reduced by successful EVL. Received: July 28, 1998/Accepted: December 18, 1998     

Increased Maternal Fasting Proinsulin as a Predictor of Insulin Requirement in Women with Gestational Diabetes

Circulating proinsulin was assessed during a 75g OGTT in 55 pregnant women who fulfilled WHO criteria for impaired glucose tolerance before the 32nd gestational week. Proinsulin was assayed retrospectively using a two-site immunoradiometric assay and immunoreactive insulin by radioimmunoassay. Of the 55 women, 19 required insulin treatment in addition to diet later in pregnancy. Fasting proinsulin concentrations were significantly higher in the 19 women who later required insulin treatment compared with the 36 women treated with diet alone (3.4 ± 0.7 vs 1.8 ± 0.2 pmol l^?1, p < 0.005). There was no difference between the treatment groups of 60 and 120 min proinsulin values during the OGTT. Fasting plasma glucose and immunoreactive insulin were similar in the insulin-treated and diet-treated women and remained similar during the OGTT. No women within the insulin-treated group had a fasting plasma proinsulin value < 1.1 pmol l^?1 in contrast with 12 women in the diet-treated group (p = 0.0123). Ten of the 19 insulin-treated women had a fasting plasma proinsulin > 2.5 pmol l^?1 compared with 8 of the 36 diet-treated women (p = 0.0346). Fasting proinsulin values early in pregnancy have prognostic implications in women with gestational diabetes.     

Increased secretion of 32,33 split proinsulin after intravenous glucose in glucose-tolerant first-degree relatives of patients with non-insulin dependent diabetes of European, but not Asian, origin

OBJECTIVE The aetiology of non-Insulin dependent diabetes Is unknown, but defective insulin Secretion is a feature. The disease also has a strong genetic basis and first-degree relatives of patients have an increased risk of future diabetes. To investigate whether β-cell dysfunction is an early feature of the disease, we studied insulin secretion In healthy first-degree relatives of patients with non-insulin dependent diabetes. DESIGN Each subject underwent a 1-hour intravenous glucose tolerance test (0·3 g/kg). PATIENTS Seventeen first-degree relatives of patients (10 of European and 7 of Asian (Indian subcontinent) origin) with normal glucose tolerance were compared with 17 matched control subjects with no family history of diabetes. MEASUREMENTS Plasma immunoreactive insulin (IRI) was measured by radiouimmunoassay, and specific insulin, intact and 32,33 split proinsulin were measured by specific immunoradiometric assays (IRMA) for the 1st phase (0–10 minutes) and 2nd phase (10–60 minutes) responses. Glucose and Intermediary metabolites were measured enzymatically. RESULTS Fasting concentrations of IRI, IRMA insulin, intact and 32,33 split proinsulin were similar in relatives and controls In each group. Fasting glucose levels were similar In European relatives and controls but lower in Asian relatives compared to their controls (mean±SE 4·9 ± 0·2 vs 5·5 ± 0·2 mmol/l, P < 0·05). Following Intravenous glucose, European relatives had similar IRI and glucose levels to their controls. Secretion of 32,33 split proinsulin was increased in European relatives compared to their controls, significantly so for 2nd phase secretion (1st phase median (range): 71 (7-352) vs 55 (17-118) pmol/l min, NS; 2nd phase: 433 (115-1459) vs 234 (55-745) pmol/l min, P < 0·05). Secretion of IRMA insulin and intact proinsulin were similar in European relatives and controls (IRMA insulin: 1st phase 2757 (700-10969) vs 2830 (632-4682) pmol/l min; 2nd phase 6387 (3006-15 865) vs 5284 (2060-18605) pmol/l min; intact proinsulin: 1st phase 31 (13-113) vs 32 (16-72) pmol/l min; 2nd phase: 174 (87-737) vs 159 (97-298) pmol/l min). European relatives had a greater percentage of proinsulin-like molecules (intact + 32,33 split proinsulin) to total insulin (sum of IRMA insulin + intact + 32,33 split proinsulin) during the 2nd phase of secretion (9·1 (5·0–11·8) vs 5·9 (4·3-12·6)%, P < 0·05). In contrast, Asian relatives had similar Secretion of IRI, IRMA Insulin, intact and 32,33 split proinsulin to their controls. Glucose disappearance (K_G) was similar in relatives and controls within each ethnic group (Europeans: relatives 725 ± 101 vs controls 668 ± 47/min; Asian: relatives 610 ± 97 vs controls 783 ± 936/min). Asian relatives had higher fasting circulating glycerol (65 ± 7 vs 44 ± 4 μmol/l, P < 0·05), non-esterlfied fatty acid (569 ± 59 vs 375 ± 64 μmol/l, P < 0·05) and 3-hydroxybuiyrate levels (147 (44-187) vs 35 (21-57) μmol/l, P < 0·01) than their controls and this persisted following intravenous glucose. This difference was not observed In the European group. CONCLUSION First-degree relatives of European patients with NIDDM possess early signs of β-cell dysfunction, with Increased and disproportionate secretion of 32,33 split proinsuiln after intravenous glucose, whilst glucose tolerance Is still normal.     

Serum proinsulin levels at fasting and after oral glucose load in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary A simple and sensitive human proinsulin radioimmunoassay system was developed using guinea pig antiproinsulin serum, which cross-reacted neither with human insulin nor C-peptide. The recognition site of the antiserum seems to be located near the junction between the B chain and C-peptide. With this assay system, we studied the serum proinsulin concentration at fasting and after an oral 100 g glucose load in 25 healthy subjects, 21 subjects with impaired glucose tolerance and 40 patients with Type 2 (non-insulin-dependent) diabetes mellitus. At fasting, serum proinsulin was 5.8±3.3 pmol/l in normal subjects as compared to 9.5±6.9 pmol/l (p<0.05) in subjects with impaired glucose tolerance and 12.6±7.5 pmol/l (p<0.001) in diabetic patients. The molar ratio of proinsulin to insulin was also increased in subjects with impaired glucose tolerance or diabetes compared to control subjects. After a 100 g oral glucose load, serum proinsulin increased more slowly than insulin. The proinsulin response after an oral glucose load was augmented in subjects with impaired glucose tolerance and diabetes, while the insulin response decreased with the elevation of fasting plasma glucose. Diabetic patients with high fasting plasma glucose had a very poor insulin response, but the proinsulin response was similar to control subjects. There was a linear correlation between summed proinsulin values and summed insulin values, but the slope of the regression line was steeper in diabetic patients than in control subjects. There was a relative increase in serum proinsulin both in subjects with impaired glucose tolerance and diabetic patients. We suggest that B cells may release ‘immature’ granules richer in proinsulin content as well as mature granules in the over-stimulated state.     

Gallbladder emptying,plasma levels of estradiol and progesterone,and cholecystokinin secretion in liver cirrhosis

Defective gallbladder emptying has been proposed as a possible accessory pathogenetic factor to explain the increased prevalence of gallstones in liver cirrhosis. In this study we have evaluated the fasting volume and the meal-stimulated emptying of the gallbladder, the plasma levels of estradiol and progesterone, and the basal and postprandial secretion of cholecystokinin in Child A cirrhotic patients compared to normal subjects. Basal (42.2±27 vs 22.8±8.4 ml) (P<0.002) and residual (8.4±8.7 vs 4.6±3.8 ml) (P<0.05) gallbladder volumes were higher in cirrhotics but neither the integrated gallbladder response to meal nor the maximal percentage of emptying was significantly different. Circulating estradiol and progesterone was slightly increased in only 1/13 and 5/13 cirrhotics, respectively. In eight cirrhotics and seven normals taken from the overall populations, the secretion of cholecystokinin was also measured. The fasting plasma level of cholecystokinin was higher in the cirrhotics (6.71±5.08 vs 2.02±0.46 pmol/liter) (P<0.01). The meal-stimulated integrated plasma cholecystokinin response also was greater in cirrhotics (438.5±615 pmol/liter/270 min) than in normals (153±170.4 pmol/liter/270 min), but this difference was not significant because of the small study population. In spite of a normal kinetics of postprandial emptying, cirrhotic patients show increased fasting gallbladder volume and increased plasma levels of basal and postprandial cholecystokinin. Circulating estradiol and progesterone do not seem to be responsible for the large gallbladder volume found in liver cirrhosis.     

Plasma homocysteine concentrations and insulin sensitivity in hypertensive subjects

Hyperhomocysteinemia is associated with several cardiovascular disease risk factors including endothelial dysfunction and abnormalities of clotting functions, which are also common features of insulin resistance syndrome observed in hypertensive patients. Recent study has shown that acute hyperinsulinemia can lower plasma homocysteine concentrations in nondiabetic but not in type 2 diabetic individuals, indicating that insulin may regulate homocysteine metabolism. To investigate the relationships between plasma homocysteine concentration and insulin sensitivity, we studied 90 Chinese hypertensive patients and a group of control subjects (n = 86) matched for age, gender, and body mass index. Fasting plasma homocysteine levels, plasma lipoprotein concentrations, plasma glucose, and insulin responses to oral glucose tolerance tests (OGTT) were determined. The results showed that fasting plasma homocysteine concentrations were significantly higher in subjects with hypertension than in those with normotension (mean ± SEM, 8.1 ± 0.6 v 6.8 ± 0.2 μmol/L; P < .05). Fasting plasma homocysteine levels correlated significantly with insulin secretion in response to OGTT even after adjustment for body mass index (P < .05) in hypertensive patients but not in normotensive individuals. However, fasting plasma homocysteine concentrations showed no correlations with steady-state plasma glucose concentration, a measurement of insulin sensitivity, during an insulin suppression test in groups of hypertensive (n = 42) and normotensive (n = 37) subjects. When the steady-state plasma glucose concentrations were divided into three tertiles, fasting plasma homocysteine concentrations showed no difference across these three groups in either hypertensive patients (8.6 ± 0.5 v 7.2 ± 0.5 v 8.4 ± 0.6 μmol/L; P = .148) or normotensive subjects (6.3 ± 0.4 v 8.0 ± 0.8 v 7.0 ± 0.8 μmol/L; P = .199). In conclusion, hypertensive Chinese subjects had higher fasting plasma homocysteine concentrations and a higher degree of insulin resistance when compared to a group of age-, gender-, and body mass index-matched normotensive individuals. Fasting plasma homocysteine levels were associated with insulin response to OGTT in hypertensives but not in normotensives. No correlation was observed between the degree of insulin resistance and plasma homocysteine levels in either the hypertensive or the normotensive group. The role of insulin in homocysteine metabolism deserves further investigation.     

Effect of insulin on renal sodium handling and renal haemodynamics in insulin-dependent (type 1) diabetes mellitus patients

The effects of insulin on renal haemodynamics and renal sodium handling were studied in eight insulindependent (type 1) diabetic patients (aged 30±3 years). Seven healthy men (aged 38±4 years) served as controls. The type 1 diabetic patients were resistant to insulin-stimulated glucose disposal as estimated by a 45% lower metabolic (P<0.01) clearance of glucose as compared with controls. However, type 1 diabetic patients were still sensitive to the distal tubular antinatriuretic effect of insulin, as indicated by an increase in distal sodium reabsorption (95.5%±0.5% to 96.9%±0.4%;P<0.05) during insulin infusion compared with controls (95.5%±0.6% to 97.4%±0.3%;P<0.05). In control subjects insulin infusion was associated with 9% increases (P<0.05) in lithium clearance and in renal plasma flow, whereas no significant increases in lithium clearance and in renal plasma flow were observed in the type 1 diabetic patients. In both groups, the changes in renal plasma flow in response to insulin infusion were positively correlated with that in lithium clearance (r=0.80 andr=0.90, respectively;P<0.05?0.01). In conclusion, the present result demonstrates an intact distal tubular sodium retaining effect in conjunction with a blunted decrease in proximal tubular sodium reabsorption following insulin infusion, which could be the result of an impaired renal vasodilation in type 1 diabetes mellitus.     

Effect of steroid-therapy on insulin sensitivity in insulin-dependent diabetic patients after kidney transplantation

Little information is available on glucose and energy metabolism in insulin-dependent diabetes mellitus (IDDM) patients receiving immunosuppression after kidney transplantation. We therefore measured insulin sensitivity (euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) in (a) eight steroid-treated IDDM patients after kidney transplantation, (b) ten IDDM patients without nephropathy, (c) ten nondiabetic patients after kidney transplantation, and (d) ten healthy control subjects. Hepatic glucose production was enhanced in both steroid-treated transplanted IDDM patients [4.8 ± 0.6 mg/kg lean body mass (LBM)·min] and IDDM patients without complications (3.8 ± 0.2 mg/kg LBM·min) compared with nondiabetic renal graft recipients and with healthy controls (2.8 ± 0.2 and 2.7 ± 0.1 mg/kg LBM·min; p < 0.01). Insulin-stimulated glucose disposal was reduced in transplanted and non-transplanted IDDM patients and nondiabetic transplanted patients versus healthy controls (6.6 ± 0.8, 5.7 ± 0.7, and 7.5 ± 0.6 versus 9.3 ± 0.6 mg/kg LBM·min; p < 0.05). This reduction was mainly due to an impairment in nonoxidative glucose metabolism, i.e., glycogen synthesis (3.1 ± 0.6, 2.7 ± 0.4, and 3.3 ± 0.5 versus 5.0 ± 0.5 mg/kg LBM·min; p < 0.05 versus healthy controls). It is concluded that IDDM patients without nephropathy show both hepatic and peripheral insulin resistance. In IDDM patients a further increase of insulin resistance caused by treatment with corticosteroids can be corrected by increased insulin doses. However, nondiabetic steroid-treated renal graft recipients show insulin resistance comparable to IDDM patients.     

Effect of pancreas transplantation and immunosuppression on proinsulin secretion

Insulin resistance and increased demand for insulin secretion occur after successful pancreas transplantation. To investigate the potential effects of immunosuppression and pancreas transplantation on fasting β-cell function, we studied fasting proinsulin and 32,33 split proinsulin secretion cross-sectionally and longitudinally in segmental pancreatic graft recipients (SPx, n = 18); in whole-pancreas graft recipients (WPx, n = 13); in nondiabetic kidney transplant recipients (Kx, n = 14) and in normal subjects (Ns, n = 14). Basal insulin secretion rates were significantly increased in SPx 15.8 (1.7), WPx 24.4 (4.5) and Kx 22.1 (2.1) vs Ns 9.7 (1.6) pmol min⁻¹ l⁻¹, p < 0.05, mean (SEM). Total proinsulin, intact proinsulin and 32,33 split proinsulin concentrations were significantly higher in all the transplanted groups than in normal subjects (p < 0.05), whereas the total proinsulin to C-peptide ratio and the 32,33 split proinsulin ratio were higher in SPx than in WPx, Kx and Ns ( < 0.05). In the longitudinal study, β-cell function in terms of proinsulin secretion remained stable for 1 year. In conclusion, fasting glucose homeostasis in pancreas-kidney transplant recipients is obtained at the expense of increased proinsulin secretion and increased insulin secretion rates, primarily induced by immunosuppression. In segmental pancreas graft recipients, increased fasting proinsulin and 32,33 split proinsulin relative to the number of β-cells transplanted indicate more stress on the residual β-cell and therefore higher secretory demand than in whole pancreas transplant recipients. © 1998 John Wiley & Sons, Ltd.     

Plasminogen Activator Inhibitor (PAI-1) Activity is Elevated in Asian and Caucasian Subjects with Non-insulin-dependent (Type 2) Diabetes but not in Those with Impaired Glucose Tolerance (IGT) or Non-diabetic Asians

In order to study the plasminogen activator inhibitor activity (PAI-1) in subjects at different risk of non-insulin-dependent diabetes and ischaemic heart disease we examined 89 subjects with diet controlled NIDDM (49 Caucasian, 40 Asian), 29 with impaired glucose tolerance (IGT) (13 Caucasian, 16 Asian), and 149 with normal glucose tolerance (67 Caucasian, 82 Asian). Diabetes was diagnosed by WHO criteria and highly specific, monoclonal antibody-based assays were used to measure insulin, intact proinsulin, and des 31,32 proinsulin. Subjects with NIDDM were significantly more obese, had more central distribution of obesity, higher fasting plasma specific insulin concentrations (NIDDM median 74 pmol l⁻¹ vs IGT 41 pmol l⁻¹, p < 0.01 and vs normals 34 pmol l⁻¹, p < 0.001) and higher PAI-1 activity than normals and those with IGT (NIDDM 23.0 ± 6.9 vs IGT 16.8 ± 5.0, p < 0.001 and vs normals 17.1 ± 6.9 AU ml⁻¹, p < 0.001). However, PAI-1 activity was not significantly different between Asian and Caucasian normals (17.5 ± 7.3 vs 16.5 ± 6.4 AU ml⁻¹, p = ns) and diabetic (22.8 ± 7.3 vs 23.1 ± 6.6 AU ml⁻¹, p = ns) subjects. In addition to relationships with obesity and plasma triglyceride, PAI-1 activity, after controlling for age, sex, body mass index, and waist–hip ratio, was related to fasting insulin (partial r = 0.22, p < 0.001), intact proinsulin (partial r = 0.36, p < 0.001), and des 31,32 proinsulin concentrations (partial r = 0.33, p < 0.001) as measured by highly specific assays. The association of PAI-1 with diabetes was weakened but remained statistically significant (p = 0.042) after controlling for age, sex, ethnicity, obesity, plasma triglyceride, and all insulin-like molecules. We conclude that, although PAI-1 activity is raised in subjects with diet-treated NIDDM, it is normal in subjects with IGT and non-diabetic Asians, populations at high risk of NIDDM and ischaemic heart disease. Raised PAI-1 activity may play an important role in the pathogenesis of macrovascular disease in subjects with NIDDM, but is unlikely to explain excess risk of ischaemic heart disease in Asians and those with impaired glucose tolerance.     

血清真胰岛素、胰岛素原与冠心病关系初探

目的：探讨冠心病（CHD）患者血清真胰岛素（TI）,胰岛素原（PI）水平,并分析这二者与其他CHD危险因子的关系。方法：对30例确诊CHD患者和30例正常人采用高度特异性的ELISA法分别检测空腹血清TI,PI和以RIA法检测空腹血清免疫活性胰岛素（IRI）水平,同时检测这二组对象的空腹和餐后2小时血糖,血脂以及血压水平,结果：CHD组IRI,TI,PI水平均高于对照组（P＜0．05）,而胰岛素敏感指数（ISI）则低于对照组（P＜0．05）,CHD组中TI,PI与年龄,BMI,血糖和血脂均有独立的相关关系,结论：CHD患者有高胰岛素血症和胰岛素抵抗状态,TI,PI分别与血糖,血脂等CHD危险因子呈群聚关系。     

Abnormal proinsulin/c-peptide ratio in juvenile diabetes

Summary B-cell function was studied in 20 diabetic children, with an age at onset of diabetes between 1–16 years (8.8 ± 4.0). Serum samples were taken before the first insulin injection and after 1, 3, 6, 9 and in a few patients after 18 months. At 3, 9, and 18 months the patients were also given a standardized breakfast load. Serum proinsulin, C-peptide, IRI and insulin antibodies (IgG) were determined. At onset 19 patients had measurable C-peptide (0.22 ± 0.17 pmol/ml; range 0.05–0.58). Proinsulin varied between 0.000–0.25 pmol/ml (0.069 ± 0.071) and at onset amounted to 31.3 ± 29.4 (0–100)% of C-peptide as compared to 3.3 ± 1.1 (1.7–6.6) in non-diabetics. A long partial remission was significantly correlated to a low proinsulin/C-peptide ratio at onset. In patients with low fasting proinsulin and no insulin antibodies, breakfast stimulation was accompanied by an increased proinsulin release at 3 and 9 months. The results suggest that abnormal proinsulin secretion is a feature of the ‘B-cell exhaustion’ complex in juvenile-onset diabetes.     

Diurnal changes of critical flicker frequency in patients with liver cirrhosis and their relationship with sleep disturbances

BackgroundWe aimed to measure the diurnal changes of critical flicker frequency in healthy subjects and cirrhotic patients and to investigate their relationship with sleep disturbance.MethodsCirrhotic patients and healthy volunteers were included. All groups completed the Pittsburgh Sleep Quality Index and a simple sleep questionnaire. Sleep disturbance was defined as a Pittsburgh Sleep Quality Index score of >5. Critical flicker frequency was measured twice a day to detect diurnal abnormalities.ResultsOverall, 59 cirrhotic patients (54.2% males, Mean Age 59 ± 11 years) and 18 controls (39.9% males, Mean Age 58 ± 9 years) were included. Sleep disturbances were more common in cirrhotics (66.1%) than controls (38.9%, p < 0.05). In cirrhotics, the critical flicker frequency was not related to decompensation. The nocturnal values were higher than the morning values in cirrhotics (64.4%), but not in controls (p < 0.0001). Additionally, sleep disturbances were more common in cirrhotics who had higher nocturnal values (p < 0.05).ConclusionsChanges in the diurnal critical flicker frequency were observed in cirrhotics but not in controls. Sleep disturbances in cirrhotics appear to be associated with deviations of the diurnal rhythm of critical flicker frequency rather than with clinical parameters such as the clinical stages of cirrhosis and the Model For End-Stage Liver Disease and Child–Pugh scores.     

The relation of proinsulin and insulin to insulin sensitivity and acute insulin response in subjects with newly diagnosed Type II diabetes: the Insulin Resistance Atherosclerosis Study

Abstract Aims/hypothesis. Proinsulin concentrations are increased relative to insulin concentrations in subjects with Type II (non-insulin-dependent) diabetes mellitus. This could be secondary to hyperglycaemia or insulin resistance or due to a defect in insulin secretion. Methods. We investigated the association between fasting insulin, intact proinsulin and the intact proinsulin: insulin ratio with insulin sensitivity, estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and with acute insulin response (AIR) in 182 newly diagnosed Type II diabetic subjects aged 40 to 69 years. None of the subjects was receiving hypoglycaemic medication. Results. Insulin sensitivity correlated inversely with fasting insulin (r _s = –0.42) and intact proinsulin (r _s = –0.32) (p < 0.001). The intact proinsulin:insulin ratio was not correlated with insulin sensitivity. AIR correlated positively with intact proinsulin (r _s = 0.23) and inversely with the intact proinsulin:insulin ratio (r _s = –0.29, p < 0.001). Fasting glucose correlated positively with intact proinsulin (r _s = 0.34) and the intact proinsulin:insulin ratio (r _s = 0.24, p < 0.001). The intact proinsulin:insulin ratio increased by decreasing AIR (quartiles of AIR from high to low: 7.8, 8.2, 9.7 and 12.1 %, p < 0.001). This association was independent of age, sex, ethnicity, body mass index, fasting glucose, and insulin sensitivity. Conclusion/interpretation. Insulin resistance (low insulin sensitivity) was not related to the intact proinsulin:insulin ratio in subjects with Type II diabetes. In contrast, both low AIR and high fasting glucose concentrations were associated with a disproportionate increase in proinsulin concentration. These results suggest that increased intact proinsulin:insulin ratio is a marker of a defect in insulin secretion in Type II diabetic subjects. [Diabetologia (1999) 42: 1060–1066] Received: 25 February 1999 and in revised form: 12 April 1999     

What is the effect of rosiglitazone treatment on insulin secretory function in insulin-resistant individuals? It depends on how you measure it

The goal of this study was to compare methods used to quantify the effect of rosiglitazone (RSG) on insulin secretory function, particularly estimates based on changes in fasting plasma glucose and insulin concentration vs daylong insulin responses to meals. To do this, we compared these measures of insulin secretion before and 3 months after RSG treatment in insulin-resistant individuals, subdivided into nondiabetic subjects (n = 29) and patients with type 2 diabetes mellitus (2DM) (n = 22). Insulin resistance was quantified by determining the steady-state plasma glucose concentration during the insulin suppression test and insulin secretory function by homeostasis model assessment of β-cell function (HOMA-β) and the total integrated daylong plasma insulin responses to mixed meals (insulin area under the curve). Baseline fasting and daylong plasma glucose concentrations were higher (P < .001) in patients with 2DM, associated with lower HOMA-β values (P < .001). However, neither fasting nor daylong insulin concentrations after mixed meals differed in the 2 groups. Insulin sensitivity improved (P < .001) after RSG administration, with decreases of 31% ± 23% and 21% ± 14% in steady-state plasma glucose concentration in nondiabetic and diabetic subjects, respectively. Although fasting and daylong plasma glucose and insulin concentrations fell (P < .001) in both groups of RSG-treated individuals, HOMA-β decreased in nondiabetic subjects and did not change in those with 2DM. In conclusion, RSG administration improved insulin sensitivity in both groups, associated with lower fasting and daylong glucose concentrations. Fasting and daylong insulin concentrations were also lower in both groups of RSG-treated subjects, but the values of HOMA-β indicated either a decrease (nondiabetics) or no change (diabetics) in insulin secretory function. These results suggest that measurements of HOMA-β may not provide a complete view of insulin secretory function, either when comparing diabetic with nondiabetic individuals or when assessing the response to RSG treatment in insulin-resistant individuals.