Changes in insulin receptor functions of the erythrocyte by treatment of non-insulin-dependent diabetes mellitus (NIDDM) patients with glibenclamide and diet control

Summary The insulin binding of erythrocytes from: (i) fifteen age-matched normal subjects, (ii) ten untreated NIDDM patients and (iii) fifteen treated (glibenclamide + hypocaloric diet) NIDDM patients (all males) has been studied. A significant decrease in specific insulin binding was observed in group (ii) which improved in cases controlled after treatment (group iii). Scatchard analysis of the results suggested that changes in insulin binding were due to alteration in the number of insulin receptors on erythrocytes. The number of insulin receptors/cell was 471 in normals, 160 in diabetics and 282 in treated diabetic subjects. No significant change in the binding affinity was observed in the three groups (1.0×10⁸, 1.2 × 10⁸ and 1.1×10⁸ M⁻¹ in normal subjects, untreated diabetics and treated diabetics, respectively). CDRI Communication No. 3807.     

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

Summary To ascertain whether the effects of diet on glucose tolerance and insulin sensitivity are mediated through changes of insulin receptors we have studied insulin binding to monocytes in 24 young volunteers (4 groups of 6) during 2 week periods of different dietary regimens. In group 1 and 2 the subjects had their usual diet plus 1000 kcal per day from sucrose or fat, respectively. Group 3 had an isocaloric diet with a low-sucrose content, while group 4 ate low-fat high carbohydrate diets. Before change of diet the total group of volunteers showed an inverse correlation between insulin binding and average daily sucrose intake (R = − 0.52, p<0.01). An excessive sucrose consumption (group 1) was associated with a reduction both of insulin binding (p<0.05) and insulin sensitivity (p<0.05). The changes of the two variables were parallel (R = 0.95, p<0.05). An abundant fat intake (group 2) was also accompanied by a decrease of insulin binding (p<0.05). However, insulin sensitivity was unaltered (p>0.1). A rise of insulin binding (p<0.05) followed the isocaloric, low-sucrose diet (group 3) whereas the insulin sensitivity was unchanged (p>0.1). After the isocaloric, low-fat diet (group 4) no significant change of insulin binding occurred (p>0.1) whereas the insulin sensitivity increased (p<0.05). We conclude that diet and especially the dietary sucrose content affect insulin binding to human monocytes. Evidence is presented that changes of insulin sensitivity following hyperalimentation of sucrose may be induced through alterations of insulin receptors.     

Use of the short-acting insulin analogue lispro in intensive treatment of Type 1 diabetes mellitus: importance of appropriate replacement of basal insulin and time-interval injection-meal

To establish whether lispro may be a suitable short-acting insulin preparation for meals in intensive treatment of Type 1 diabetes mellitus (DM) in patients already in chronic good glycaemic control with conventional insulins, 69 patients on intensive therapy (4 daily s.c. insulin injections, soluble at each meal, NPH at bedtime, HbA_1c <7.5 %) were studied with an open, cross-over design for two periods of 3 months each (lispro or soluble). The % HbA_1c and frequency of hypoglycaemia were assessed under four different conditions (Groups I–IV). Lispro was always injected at mealtime, soluble 10–40 min prior to meals (with the exception of Group IV). Bedtime NPH was continued with both treatments. When lispro replaced soluble with no increase in number of daily NPH injections (Group I, n = 15), HbA_1c was no different (p = NS), but frequency of hypoglycaemia was greater (p < 0.05). When NPH was given 3–4 times daily, lispro (Group II, n = 18), but not soluble (Group III, n = 12) decreased HbA_1c by 0.35 ± 0.25 % with no increase in hypoglycaemia. When soluble was injected at mealtimes, HbA_1c increased by 0.18 ± 0.15% and hypoglycaemia was more frequent than when soluble was injected 10–40 min prior to meals (Group IV, n = 24) (p < 0.05). It is concluded that in intensive management of Type 1 DM, lispro is superior to soluble in terms of reduction of % HbA_1c and frequency of hypoglycaemia, especially for those patients who do not use a time interval between insulin injection and meal. However, these goals cannot be achieved without optimization of basal insulin. © 1998 John Wiley & Sons, Ltd.     

Ontogenesis of insulin receptors in human cerebral cortex.

This study examines the ontogenesis of insulin receptors in human cerebral cortex. Synaptosomal membrane fraction was obtained after subcellular fractionation of human brain tissue. The 24 cases studied were classified according to the statistical differences found in: Group I, pre-term, up to 30 weeks of gestation; group II, full-term and newborns; group III from one year to adulthood. Scatchard plots of insulin binding to brain membranes were curvilinear and showed a decrease in insulin receptor number as a function of age with slight differences in affinity. Receptor number were 3.0 +/- 0.8 pmol/mg in Group I, 0.6 +/- 0.14 pmol/mg and 0.2 +/- 0.024 pmol/mg in Groups II and III respectively. Values of 5'nucleotidase and Na+ K+ ATPase activities, were similar in all groups, which indicates that the purity of the fraction used for binding was similar in each group. According to the ontogenic profile in insulin binding described in this work, it may be assumed that the higher concentration of insulin receptors in human brain during the fetal period can determine some insulin action in this early stage of maturation, even though the functionality of these receptors remains to be elucidated.     

Increased insulin sensitivity and cellular insulin binding in obese diabetics following treatment with glibenclamide.

The aim of the present study was to examine the effect of glibenclamide on the insulin receptors, the insulin sensitivity and the insulin secretion in obese non-ketotic diabetics. Two groups of 9 obese diabetics were studied before and after 10 days' treatment with a 1200 kcal's diet and a 1200 kcal's diet + 10 mg/day of glibenclamide, respectively. In the group treated with diet alone we found no significant alteration of the insulin secretion pattern (P greater than 0.1). However, the insulin sensitivity increased 37% (P less than 0.01). Furthermore, the insulin binding to monocytes increased (P less than 0.01) due to a 36% rise of the binding affinity. In the group treated with glibenclamide and diet the insulin secretory pattern was unchanged, too (p greater than 0.1). The insulin sensitivity, however, increased 83% (P less than 0.01). Moreover, the insulin binding was raised (P less than 0.01) as a result of a 80% rise of the number of insulin receptors. In 4 patients who were treated with diet (1200 kcal/day) plus glibenclamide and in 5 patients who were treated with diet alone (1200 kcal/day) the insulin binding to monocytes was studied during treatment for 1 year. After 1 year we found a significantly (P less than 0.005) higher cellular insulin binding in the glibenclamide treated patients compared to the patients who got diet alone. We conclude that 1) the augmentation of the insulin sensitivity is of great importance for the normalization of the diabetic state in obese, 2) the increase in insulin binding may be of importance for the increase in insulin sensitivity, 3) glibenclamide appears to enhance the insulin sensitivity through an increase in the number of insulin receptors.     

Ischemic ventricular fibrillation: The importance of being spontaneous

Although the energy level required to defibrillate normal myocardium is low and constant, as determined from studies of induced ventricular fibrillation, little is known of the specific energy requirements in regionally ischemic hearts for spontaneous or induced ventricular fibrillation. In this study the lowest energy threshold for defibrillation was determined in 10 open chest dogs with reversible 10 minute coronary occlusions at various sites for each of 44 events of ventricular fibrillation, using apical and superior vena caval electrodes with a generator providing variable output of 1 to 30 watt seconds. The ischemic mass, quantitated from postmortem angiographic and planimetric data, was 52 ± 9 percent (mean ± standard deviation) of the left ventricle in dogs with induced ventricular fibrillation (Group I), 52 ± 12 percent in dogs with spontaneous ventricular fibrillation after occlusion (Group II) and 54 ± 9 percent in dogs with spontaneous ventricular fibrillation after reperfusion (Group III). Defibrillation thresholds in watt seconds were 9 ± 7 in Group I (n = 12), 19 ± 10 in Group II (n = 13) and 18 ± 10 in Group III (n = 19). (Group I versus Groups II and III, probability [p]<0.025). In nonischemic hearts, the defibrillation threshold was 3 ± 2 (n = 32) (p <0.001 compared with values in Group I, II or III). Thus, despite similar masses of ischemia, twice as much energy was required for defibrillation of spontaneous ventricular fibrillation (whether after occlusion or reperfusion) as for induced ventricular fibrillation, suggesting that these conditions are caused by different metabolic or pathologic derangements. Such differences should be considered in assessing interventions such as drug therapy designed to inhibit the repetitive ventricular response and in design of implantable defibrillators.     

NIDDM: a rapid progressive disease Results from a long-term,randomised, comparative study of insulin or sulphonylurea treatment

Summary The objective of the present study was to assess the relative efficacy of insulin or glibenclamide treatment for non-insulin-dependent diabetes mellitus (NIDDM) over 42 months. We performed a randomised, controlled trial allocating patients treated with diet and oral antihyperglycaemic agents to treatment with glibenclamide or insulin to achieve HbA_1c levels under 7.5 %. We included 36 subjects with established NIDDM of more than 2 years' duration. Mean HbA_1c levels were significantly reduced in patients allocated to insulin treatment from 9.1 ± 1.4 % before the start to 7.8 ± 1.3 % (p< 0.05) after 1 year, and did not change significantly thereafter throughout the study period. Mean HbA_1c levels increased during the study in the patients allocated to glibenclamide treatment, and 11 of 18 patients had to be switched to insulin treatment due to increasing hyperglycaemia (HbA_1c > 10 %). Mean body weight increased in the subjects allocated to insulin by 7.2 ± 4.1 kg during the study period. In conclusion, insulin was more effective than glibenclamide treatment in obtaining control over hyperglycaemia in these patients, and once improved, glycaemic control did not deteriorate over 42 months in the insulin-treated group. Two thirds of the patients allocated to glibenclamide treatment had to be given insulin due to inadequate glycaemic control. [Diabetologia (1996) 39: 1629–1633]     

Effects of Insulin on Body Composition in Patients with Insulin-dependent and Non-insulin-dependent Diabetes

Insulin is used to control blood glucose but may have an adverse effect on the amount and distribution of fat mass and other cardiovascular risk factors. To test this hypothesis the effect of insulin therapy on blood glucose, body composition, and lipid levels was measured during 6 months in 9 patients with newly diagnosed insulin-dependent (Type 1) diabetes mellitus (IDDM) and 15 patients with non-insulin dependent (Type 2) diabetes (NIDDM) and secondary failure of therapy with oral hypoglycaemic agents. Both groups received similar daily doses of insulin (∼0.6 units kg⁻¹ day⁻¹). Glycaemic control improved during 6 months treatment in both groups, although the reduction in HbA_1c was greater in IDDM (5.2 ± 0.7 %) than in NIDDM (2.0 ± 0.4 %, p < 0.001). All parameters of the lipid profile improved in IDDM but not in NIDDM. Body weight, lean mass, and fat mass, measured by dual energy x-ray absorptiometry, increased at 1 month in IDDM but not in NIDDM. By 6 months, body weight had increased more in IDDM than NIDDM (9.1 ± 1.2 vs 3.77 ± 0.5 kg, p < 0.01). The increase in weight was predominantly lean mass in IDDM (60.4 ± 9.3 %) and fat mass in NIDDM (59.9 ± 8.4 %). The increase in lean mass was greater in IDDM than NIDDM (5.6 ± 1.1 vs 1.4 ± 0.3 kg, p < 0.001). Fat mass increased by similar increments in IDDM and NIDDM (3.4 ± 0.8 vs 2.4 ± 0.5 kg, p = ns) and was predominantly an increase in trunk fat (IDDM: 2.3 ± 0.6 kg, NIDDM: 2.0 ± 0.4 kg, p = ns). The central/peripheral fat mass ratio prior to treatment was lower in IDDM than NIDDM (0.64 ± 0.05 vs 1.09 ± 0.09, p < 0.01) and then increased in IDDM by 0.32 ± 0.15 (p = 0.07) and in NIDDM by 0.22 ± 0.06 (p < 0.001). In conclusion, insulin therapy is associated with weight gain in both IDDM and NIDDM. In the former, weight gain reflects increases in lean mass whereas in NIDDM it reflects an increase in trunk fat mass. It remains to be determined whether this trend to central obesity partly offsets other benefits of insulin therapy in NIDDM.     

Transient Effect of the Combination of Insulin and Sulfonylurea (Glibenclamide) on Glycemic Control in Non-Insulin Dependent Diabetics Poorly Controlled with Insulin Alone

ABSTRACT In a double-blind cross-over study we compared the effects of insulin plus glibenclamide, 5 mg twice daily, with insulin plus placebo during 8-week periods on metabolic parameters in 13 non-insulin dependent diabetic (NIDDM) patients poorly controlled with insulin alone. The combination therapy improved diabetic control as assessed by fasting blood glucose (p<0.001), 24-hour urinary glucose (p<0.01) and glycohemoglobin (HbA₁) concentrations (p<0.05 at week 12). The effect tended to cease with time. Significantly higher C-peptide values were found during combination treatment than during insulin-placebo (p<0.01) and the changes in fasting C-peptide concentrations correlated positively with the changes in HbA₁ concentrations (r=0.56, p<0.05). There was no difference in glucagon concentrations, insulin binding to erythrocytes or insulin sensitivity between the two study periods. Neither did the combination therapy influence blood lipids significantly. The present study shows that the combination of insulin and glibenclamide may be of limited value in the treatment of NIDDM patients poorly controlled with insulin alone. However, thus far the long-term results are uncertain. In the absence of significant effects on insulin binding and insulin sensitivity, the improved diabetic control seems to be explained, at least partly, by glibenclamide-induced stimulation of insulin secretion.     

Quantitative and qualitative differences in basal and glucose- and arginine-stimulated insulin secretion in healthy subjects and different stages of NIDDM

Summary To determine quantitative and qualitative differences in insulin secretion equimolar amounts of glucose and arginine were infused in 9 healthy subjects, in 8 individuals each with obesity without and with impaired glucose tolerance, and in non-obese and obese non-insulin-dependent diabetic patients (NIDDM). Insulin secretion was calculated after individual determination of metabolic clearance rate of C-peptide (MCRcp) both as the area under the C-peptide concentration curve times MCRcp, and by a mono-compartment mathematical model, both yielding identical results. MCRcp fell consistently with increasing C-peptide infusion rate (e.g.: healthy subjects: C-peptide, 10 nmol/h, 4.2±0.4; 20 nmol/h, 3.3±0.3; 30 nmol/h, 3.1±0.2 ml/kg · min; p<0.05 to p<0.01). Basal insulin secretion was 2.1-fold greater in the obese with impaired glucose tolerance than in healthy subjects, but was unchanged in non-obese NIDDM. Glucose and arginine triggered insulin release was greater than in healthy subjects at almost identical area under the respective substrate concentration curve (AUC/kg body weight) in obese subjects without (2-fold) and with impaired glucose tolerance (4-fold), and in NIDDMs following i.v. arginine (2-fold). The mean ratio of incremental insulin release to i.v. glucose and arginine was smaller in NIDDM (normal weight, 1.3±0.4; obese, 1.0±0.2) than in healthy (2.0±0.3), or obese subjects with impaired glucose tolerance (2.8±0.7). Stimulated C-peptide/insulin ratio was reduced in all patientsvs that in healthy subjects (p<0.05). We conclude that (a) MCR of C-peptide is in part a saturable process; (b) insulin clearance may be impaired in obesity and NIDDM; and (c) insulin secretion differs in obese states and NIDDM both quantitatively and qualitatively, and thereby separates the two disorders as different entities. In addition, quantitation of insulin release in obese states may also help (d) to better define primary algorithms for insulin replacement in normal- and overweight insulin-dependent diabetic patients.     

Effect of insulin treatment on circulating islet amyloid polypeptide in patients with NIDDM

The objective was to evaluate the effect of insulin treatment on circulating islet amyloid polypeptide (IAPP). Twelve patients with NIDDM and secondary failure were studied on oral agents and then switched to insulin treatment. Fasting and postprandial IAPP concentrations were measured on oral treatment and on insulin treatment. In 5 of the patients no postprandial concentrations were determined. In the 7 patients who were investigated both fasting and postprandially the fasting IAPP concentration was 6.5 ± 1.2 pmol l⁻¹ (mean ± SEM) during oral treatment with a rise to 13.5 ± 3.1 90 min after breakfast (p = 0.028). On insulin treatment HbA_lc decreased from 8.6 ± 0.5 to 7.5 ± 0.4 % (p< 0.03) and plasma C-peptide concentration was significantly lowered (p< 0.01). There was a close correlation using simple regression between the per cent change of IAPP concentration and the per cent change of C-peptide concentration during this period (r = 0.88; p< 0.01). In the total patient material of 12 patients there was a significant correlation using simple regression analysis between per cent change of IAPP concentration and per cent change of C-peptide concentration using all 48 measurements available (r = 0.58: p< 0.001). These data suggest that secretion of IAPP is lowered when endogenous insulin secretion is lowered by administration of exogenous insulin in patients with NIDDM. Thus, if IAPP secretion has a pathogenetic role in the development of beta cell failure in NIDDM, insulin treatment might delay this deterioration. © 1997 by John Wiley & Sons, Ltd.     

Insulin resistance is associated with high plasma ouabain-like immunoreactivity concentration in NIDDM

Summary The aim of the present study was to elucidate the pathophysiologic significance of circulating ouabain as a link between insulin resistance (IR) and hypertension (HT) in NIDDM. Euglycaemic (4.5 mmol/l) hyperinsulinaemic (360–580 pmol/l) clamping was performed using an artificial endocrine pancreas. Plasma ouabain-like immunoreactivity (OLI) was determined by radioimmunoassay using a highly specific antibody to ouabain. HT was defined as systolic blood pressure > 140 mm Hg and/or diastolic > 90 mm Hg or being treated with antihypertensive agents. The values (mean ± SEM) of glucose infusion rate (GIR) and plasma OLI were compared among the four groups classified using IR and HT as factors. Group I (IR−/HT−, n = 15):GIR 7.20 ± 0.36 mg · kg⁻¹· min⁻¹, OLI 130.8 ± 20.9 pmol/l, which was not different from that in eight normal control subjects (7.69 ± 0.40 mg · kg⁻¹· min⁻¹ and 142.6 ± 32.3 pmol/l, respectively); Group II (IR−/HT+, n = 13): 5.89 ± 0.36 mg · kg⁻¹· min⁻¹, 172.5 ± 35.0 pmol/l; Group III (IR+/HT−, n = 14) 1.91 ± 0.28 mg · kg⁻¹· min⁻¹, 576.6 ± 161.5 pmol/l (p < 0.01 vs Group I and II); Group IV (IR+/HT+, n = 15) 1.79 ± 0.22 mg · kg⁻¹· min⁻¹, 703.1 ± 170.1 pmol/l (p < 0.01 vs Group I and II), respectively. Six of 57 NIDDM patients studied exhibited very high (> 1500 pmol/l) plasma OLI concentrations, showed marked insulin resistance and were all hypertensive. When analysed as a whole, plasma OLI was negatively correlated with GIR (p < 0.001), but was not correlated with arterial blood pressure. These results demonstrate that plasma concentration of OLI is closely associated with the severity of IR but not with blood pressure elevation. It is, however, possible that in some fraction of NIDDM patients with insulin resistance, the elevation of blood pressure may be causally related to circulating OLI. [Diabetologia (1995) 38: 792–797] Received: 13 September 1994 and in revised form: 9 December 1994     

Miscibility of semisynthetic human ultralente insulin with short-acting insulin in insulin-dependent diabetic patients

Summary In 15 insulin dependent diabetics (IDDM), treated with human monocomponent insulin, the absorption of Actrapid HM mixed with Ultratard HM was evaluated. Thirty U of Ultratard HM and 10 U of Actrapid HM were injected separately or together immediately after mixing. Free insulin and plasma glucose (PG) were measured four hours after the administration. Free insulin levels were significantly higher after 15 (2p<0.01), 60 (2p<0.05) and 90 min (2p<0.005) when the two insulins were injected separately. PG values were significantly lower (2p<0.05) (7.63±4.06 mmol/1) at 120 min when the two insulins were injected separately compared to the mixture (9.45±4.22 mmol/l). In conclusion, mixing Ultratard HM and Actrapid HM 3:1, we observed a decrease of early Actrapid absorption and a slower lowering of PG values.     

The combination of insulin and sulphonylurea in the treatment of secondary drug failure in patients with type II diabetes

Thirteen patients (6 females and 7 males) who were secondary failures on oral drug therapy were randomly allocated to either 2 months of treatment with insulin + glibenclamide or insulin + placebo. Thereafter the treatment schedules of the two groups were switched over for another two months. The combination of insulin and glibenclamide was more effective in lowering the fasting blood glucose (P = 0.026) and 24 h urine glucose (P = 0.042) than the combination of insulin and placebo. The combination therapy with insulin and glibenclamide revealed higher basal (P = 0.021) and glucagon-stimulated C-peptide concentrations (P = 0.037) than therapy with insulin and placebo. However, insulin binding to erythrocytes did not differ between the two study periods. The results indicate that the addition of glibenclamide to insulin in type II diabetics poorly controlled by oral antidiabetics alone may slightly improve diabetic control. The mechanism of this action is due at least partly to sulphonylurea-induced stimulation of endogenous insulin secretion. The effectiveness of the combination treatment during long-term therapy still remains to be proven, however.     

A long-term,randomized, comparative study of insulin versus sulfonylurea therapy in type 2 diabetes

Abstract. Objectives. To study the effect of insulin and sulfonylurea (SU) therapy on glycaemic control, insulin resistance and cardiovascular risk factors in type 2 diabetic subjects. Design. A prospective, parallel, randomized, controlled, long-term study. Setting. Outpatient clinic in tertiary referral centre. Subjects. Thirty-six type 2 diabetic subjects treated with diet and SU, aged 44–69 years and a duration of diabetes of between 2 and 14 years. Interventions. Individually adjusted doses of insulin and glibenclamide. Main outcome measures. Glycosylated haemoglobin (HbA_1c), insulin resistance (euglycaemic glucose clamp), levels of lipids, lipoproteins and blood pressure. Results. Glycaemic control improved during insulin treatment, but deteriorated on SU; HbA_1c levels differed significantly between groups after 12 months of therapy (mean ± SEM 7.9 ± 0.3 vs. 9.5 ± 0.4%. P = 0.004). Body mass index increased significantly during insulin treatment (26.4 ± 0.7 to 27.8 ± 0.7 kg/m², P = 0.0001) and 30% of this increase was a result of an increase in lean body mass. The total glucose disposal rate showed a small increase in the insulin group. Levels of triglycerides and apolipoprotein B were significantly reduced during insulin treatment (1.8 ± 0.2 to 1.5 ± 0.2 mmol L^?1, P = 0.03 and 1.58 ± 0.1 to 1.40 ± 0.08 g L^?1, P = 0.003), and insulin prevented a reduction in the levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-1 and an increase in Lp(a) lipoprotein observed in the SU group. Blood pressure levels did not change during therapy. Conclusions. Insulin therapy was superior to SU treatment in achieving good metabolic control. Despite a modest improvement in cardiovascular risk factors in the insulin-treated group, no significant differences were observed between the groups after 1 year's treatment.     

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.     

Effect of BMI,insulin dose and number of injections on glycaemic control in insulin-using diabetic patients

Background: Strict glucose control is essential to the prevention of diabetic complications. The level of glycaemic control in insulin-treated patients with diabetes mellitus (DM) in a routine clinical setting is not known.Methods: In a cross-sectional survey comprising 8 hospitals in the Rijnmond area, The Netherlands, age, body mass index (BMI), insulin dose, number of injections, and HbA1_c were scored in 712 patients with insulin-dependent DM (IDDM) and 462 patients with non-insulin-dependent DM (NIDDM).Results: In IDDM and NIDDM patients, respectively, age (mean ± SD) was 40 ± 17 and 65 ± 12 years, BMI was 24.1 ± 3.5 and 27.3 ± 4.1 kg/m², daily insulin dose was 49 ± 18 and 44 ± 18 U (P < 0.001). Intensive therapy (≥ 4 injections or continuous subcutaneous insulin infusion) was used in 59% of IDDM and 13% of NIDDM patients. HbA1_c below the upper normal limit was achieved in 11% of the patients, and within 20% above the upper normal limit in 37%. Obesity was positively associated with HbA1_c in NIDDM patients (P < 0.01). A higher insulin dose was associated with higher HbA1_c in both IDDM and NIDDM patients (P < 0.01).Conclusions: Good glycaemic control was established in 37% of our patients. Intensive insulin treatment and higher insulin dose did not improve glucose regulation. Obesity is a risk factor for poor glycaemic control.     

Anthropometric studies in diabetes in the Tropics

Summary Anthropometric studies were carried out in three groups of diabetics seen in southern India, namely fibrocalculous pancreatic diabetes (FCPD) (n=49) (a subtype of malnutrition related diabetes), insulin dependent diabetes mellitus (IDDM) (n=55) and non-insulin dependent diabetes mellitus (NIDDM) (n=104). Both FCPD and IDDM had significantly lower body mass index, skinfold thickness (triceps, biceps, subscapular and suprailiac), mid-arm circumference and fat mass compared to controls and NIDDM patients, (p<0.001 for all parameters). FCPD and IDDM males did not show any significant differences in any of the anthropometric parameters studied. Among the females, FCPD had lower triceps skinfold measurements (p=0.007) and mid-arm circumferences (p<0.05) compared to IDDM patients. Patients with NIDDM did not show any significant difference compared to the control group. This study shows that both FCPD and IDDM patients have lower body mass and fat mass compared to NIDDM patients and control subjects.     

Remission from insulin dependence induced by continuous subcutaneous insulin infusion (CSII) in type I,newly diagnosed diabetics: Role of some hormonal and immunologic factors

Summary Optimal and early control of recent onset, type I diabetes by intensive insulin therapy has been reported to allow insulin withdrawal in about two thirds of subjects treated. We used continuous s.c. insulin infusion (CSII) in the attempt to induce a temporary remission of insulin dependence in 18 newly diagnosed young adult diabetics. After 10 days of optimized glycometabolic control, insulin infusion was stopped and patients were switched to glibenclamide (15 mg/die) plus metformin (1 g/die). Diabetics were considered in remission of insulin dependence when their metabolic control fulfilled the following criteria for at least 3 months: absence of glycosuria, pre- and post-prandial blood glucose ≤ 120 and 180 mg/dl, respectively, HbA_lc ≤ 7%. Insulin therapy could be discontinued for periods of over three months in 11 subjects (61%) and for as long as 18 months in one case. Insulin requirement during CSII was slightly higher in non-remitters (NR) than in remitters (R): 0.36–0.64vs 0.26–0.41 U/kg/die. After 24 months from CSII, R still showed lower insulin requirement (0.35–0.42 U/kg/die) than NR (0.55–0.75 U/kg/die). Further, the role of some hormonal and immunologic factors was investigated. Plasma C-peptide and glucagon were measured, fasting and 2h after each meal, both on admission and immediately after CSII, when patients were switched to oral therapy. No difference in hormone levels could be detected on admission, whereas, after CSII, mean post-prandial increase of C-peptide over basal was significantly higher in R than in NR (1.18 ± 0.37vs 0.22 ± 0.16 ng/ml, p<0.001). Finally, blood distribution of T, B, T4 and T8 lymphocyte subsets was measured in all patients, both before and after CSII. The T4/T8 ratio was found to be significantly increased in NR group patients (3.19 ± 0.45vs 2.41 ± 0.23, p<0.005). The immunologic pattern did not show any significant modification after ten days of optimized control by CSII. In conclusion, immunologic background and residual B-cell function may be associated with a different susceptibility to remission from insulin therapy in newly diagnosed young adult diabetics.     

Decreased insulin binding in asian indian women with gestational diabetes mellitus

Summary Insulin binding to erythrocyte insulin receptors was studied in 10 women with gestational diabetes and compared with 10 matched, normal, pregnant women and 10 normal, non-pregnant controls, with no family history of diabetes. Pregnant women had higher mean fasting and postglucose plasma immunoreactive insulin (IRI) compared to non-pregnant controls (p<0.001). Women with gestational diabetes had higher mean fasting and post-glucose plasma glucose levels and a lower mean specific binding of insulin when compared with the other two groups (p<0.001). The decreased insulin binding was significant only at lower insulin concentrations (0.2 – 2 ng/ml) when compared with those of normal pregnant women (p<0.01), suggesting decreased receptor affinity with no change in receptor number. In addition, an increased mean ED₅₀ value for 50% inhibition of maximal binding and a lower mean average affinity constant K_e (empty site) obtained in gestational diabetes in comparison to the other two groups also suggested decreased affinity of the receptor. The finding that pregnancy with normal glucose tolerance was not accompanied by changes in insulin binding as against decreased insulin binding and affinity observed in gestational diabetes suggested a pathogenetic role for impaired insulin binding as one of the factors responsible for insulin resistance and hyperglycemia in gestational diabetes.