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.     

Metabolic Abnormalities in Offspring of NIDDM Patients with a Family History of Diabetes Mellitus

NIDDM appears to be an inherited condition. Our aim was to identify early metabolic abnormalities in non-diabetic offspring with one NIDDM parent and with a strongly positive (n = 58, age 27.8 ± 7.0 years) or a negative family history (n = 38, age 27.4 ± 6.7 years) of diabetes. These were compared with 31 offspring of non-diabetic parents (age 26.9 ± 5.5 years). After an overnight fast, blood was taken for glucose, insulin, C-peptide, insulin receptors, and lipids. All the subjects underwent a 75 g oral glucose tolerance test. The positive family history group had significantly higher fasting levels of triglycerides (1.09 ± 0.24 vs control subjects: CS: 0.93 ± 0.16 mmol l⁻¹, p < 0.001), insulin (102.8 ± 46.4 vs CS: 77.5 ± 32.4 pmol l⁻¹, p < 0.01) and C-peptide (0.69 ± 0.22 vs CS: 0.61 ± 0.19 nmol l⁻¹, p < 0.05) and lower numbers of insulin receptors per red cell (9.1 × 10³ (4.5–18.1, 95 % confidence intervals) vs CS: (11.2 × 10³ (6.3–19.9)), p < 0.01, despite similar blood glucose levels. After a glucose challenge (120 min), the increases in both insulin and C-peptide concentrations were significantly greater in the positive family history group (289.2 ± 214.1 pmol l⁻¹, 2.23 ± 1.48 nmol l⁻¹), respectively, than in CS (192.4 ± 170.3 pmol l⁻¹, p < 0.05) (1.54 ± 0.99 nmol l⁻¹ p < 0.01), respectively. No significant differences were found in fasting and post-challenge glucose levels. The negative family history group had significantly lower numbers of insulin receptors 9.4 × 10³ (4.1–15.2) compared with CS (p < 0.05). Insulin sensitivity was significantly reduced in the positive family history group (41.6 %) compared with control subjects (51.9 %), p < 0.01. The results strongly support the familial basis of the disease.     

Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients

Summary We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 ± 1.7 vs 29.6 ± 1.6 years, BMI: 25.1 ± 1.0 vs 25.1 ± 0.9 kg/m²). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 ± 0.2 [range: 3.2–7.0] vs 5.5 ± 0.2 [3.7–7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 ± 0.04 vs 0.34 ± 0.04 10^–4 min^–1 per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 ± 0.7 [3.9–17.0] vs 7.5 ± 0.3 [5.7–9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the control subjects (9.8 mmol/l). These “hyperglycaemic” relatives had diminished first phase insulin secretion (?1) both before and during dex compared with the “normal” relatives and the control subjects (pre-dex ?1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6 ± 3.6 (p < 0.05), post-dex ?1: 22.2 ± 6.6 vs 48.0 ± 7.2 and 46.2 ± 6.6 respectively (p < 0.05) pmol · l^–1· min^–1 per mg/dl). However, Si was similar in “hyperglycaemic” and “normal” relatives before dex (0.65 ± 0.10 vs 0.54 ± 0.10 10−4 · min^–1 per pmol/l) and suppressed similarly during dex (0.30 ± 0.07 vs 0.30 ± 0.06 10−4 · min^–1 per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent development of high 2-h post-dex OGTT plasma glucose levels (R ² = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state. [Diabetologia (1997) 40: 1439–1448] Received: 20 January 1997 and in final revised form: 17 July 1997     

Assessment of insulin sensitivity and secretion with the labelled intravenous glucose tolerance test: improved modelling analysis

Summary A new modelling analysis was developed to assess insulin sensitivity with a tracer-modified intravenous glucose tolerance test (IVGTT). IVGTTs were performed in 5 normal (NGT) and 7 non-insulin-dependent diabetic (NIDDM) subjects. A 300 mg/kg glucose bolus containing [6,6-²H₂]glucose was given at time 0. After 20 min, insulin was infused for 5 min (NGT, 0.03; NIDDM, 0.05 U/kg). Concentrations of tracer, glucose, insulin and C-peptide were measured for 240 min. A circulatory model for glucose kinetics was used. Glucose clearance was assumed to depend linearly on plasma insulin concentration delayed. Model parameters were: basal glucose clearance (Cl_b), glucose clearance at 600 pmol/l insulin concentration (Cl₆₀₀), basal glucose production (P_b), basal insulin sensitivity index (BSI = Cl_b/basal insulin concentration); incremental insulin sensitivity index (ISI = slope of the relationship between insulin concentration and glucose clearance). Insulin secretion was calculated by deconvolution of C-peptide data. Indices of basal pancreatic sensitivity (PSI_b) and first (PSI₁) and second-phase (PSI₂) sensitivity were calculated by normalizing insulin secretion to the prevailing glucose levels. Diabetic subjects were found to be insulin resistant (BSI: 2.3 ± 0.6 vs 0.76 ± 0.18 ml · min^–1· m^–2· pmol/l^–1, p < 0.02; ISI: 0.40 ± 0.06 vs 0.13 ± 0.05 ml · min^–1· m^–2· pmol/l^–1, p < 0.02; Cl₆₀₀: 333 ± 47 vs 137 ± 26 ml · min^–1· m^–2, p < 0.01; NGT vs NIDDM). P_b was not elevated in NIDDM (588 ± 169 vs 606 ± 123 μmol · min^–1· m^–2, NGT vs NIDDM). Hepatic insulin resistance was however present as basal glucose and insulin were higher. PSI₁ was impaired in NIDDM (67 ± 15 vs 12 ± 7 pmol · min^–1· m^–2· mmol/l^–1, p < 0.02; NGT vs NIDDM). In NGT and in a subset of NIDDM subjects (n = 4), PSI_b was inversely correlated with BSI (r = 0.95, p < 0.0001, log transformation). This suggests the existence of a compensatory mechanism that increases pancreatic sensitivity in the presence of insulin resistance, which is normal in some NIDDM subjects and impaired in others. In conclusion, using a simple test the present analysis provides a rich set of parameters characterizing glucose metabolism and insulin secretion, agrees with the literature, and provides some new information on the relationship between insulin sensitivity and secretion. [Diabetologia (1998) 41: 1029–1039] Received: 17 September 1997 and in final revised form: 28 April 1998     

Increased prothrombin fragment 1+2 and D-dimer in first-degree relatives of type 2 diabetic patients

To evaluate whether or not activated coagulation is present in the preclinical phases of type 2 diabetes mellitus, we studied 46 non-diabetic first-degree relatives of type 2 diabetic patients and 21 matched controls with no family history of diabetes. We determined the plasma levels of prothrombin fragment 1+2, D-dimer, fibrinogen, plasminogen activator inhibitor type 1, tissue plasminogen activator, von Willebrand factor and coagulation factors VII and VIII. Glucose tolerance, beta-cell function and insulin sensitivity were assessed in all subjects by a continuous glucose infusion of 5 mg·kg ideal body weight^–1·min^–1 for 60 min with model assessment of glucose, insulin and C-peptide values. Plasma levels of prothrombin fragment 1+2 (median 1.24 vs 0.68 nmol·1^–1;P=0.0001) and D-dimer (331 vs 254 g·l^–1 UEF;P=0.018) were higher in relatives, without significant differences in the other haemostatic variables. Relatives showed higher fasting (5.5 vs 4.9 mmol·l^–1,P=0.004) and post-infusion (9.3 vs 8.3 mmol·l^–1,P=0.02) serum glucose, no differences in insulin or C-peptide levels, lower beta-cell function (122% vs 147%;P=0.02) and no significant differences in insulin sensitivity. Fifteen relatives were glucose-intolerant and had lower beta-cell function and insulin sensitivity than glucose-tolerant relatives. Both subsets of relatives exhibited higher levels of prothrombin fragment 1+2 and D-dimer than control subjects. Thus, first-degree relatives of type 2 diabetic patients present an activated coagulation, even in the absence of minor degrees of glucose intolerance. These abnormalities can play a role in the pathogenesis of cardiovascular diseases frequently seen at diagnosis of type 2 diabetes.This work was presented at the 31 st meeting of the European Association for the Study of Diabetes in Stockholm, Sweden, 12–16 September 1995, and published in an abstract form:Diabetologia (1995) 38:A257     

Similar Physiological and Symptomatic Responses to Sulphonylurea and Insulin Induced Hypoglycaemia in Normal Subjects

There is little information concerning the physiological response to hypoglycaemia induced by sulphonylureas. We compared the physiological and symptomatic responses to insulin and tolbutamide induced hypoglycaemia in 8 normal subjects. While infusing either insulin or tolbutamide, we used a glucose clamp to maintain blood glucose at 4.5 mmol l⁻¹ for 30 min and lowered it to 2.9 mmol l⁻¹ for a further 30 min. Mean peripheral insulin levels during the insulin infusion arm in comparison with the tolbutamide infusion were not significantly different during the euglycaemic plateau: 106 ± 4 vs 77 ± 15 mU l ⁻¹ (mean ± SEM) (mean difference 29 mU l⁻¹, 95 % CI −22 to 80; p = NS) but were greater during the hypoglycaemic plateau: 106 ± 3.5 vs 21.0 ± 4.0 mU l⁻¹ (mean difference 85 mU l⁻¹, 95 % CI 72 to 98; p < 0.0001). Portal insulin concentrations, calculated from C-peptide data were not significantly different during the euglycaemic plateau with insulin as compared to tolbutamide. However, during hypoglycaemia portal insulin concentrations were significantly higher 15 min from the start of the plateau, during insulin infusion. During hypoglycaemia induced by either insulin or tolbutamide there were similar peak responses of glucagon: 124 ± 14 vs 128 ± 7 ng l⁻¹ (mean difference −4, 95 % CI −39 to 31; p = NS) and adrenaline: 2.9 ± 0.4 vs 2.8 ± 0.3 nmol l⁻¹, (mean difference 0.1, 95 % CI −0.9 to 1.0; p = NS). Increases in tremor and sweating and deterioration in reaction time were similar during both periods of hypoglycaemia as were increases in total: 18.5 ± 1.4 vs 19.6 ± 2.2 (mean difference −1.0, 95 % CI −3.8 to 1.8; p = NS) and autonomic: 8.9 ± 0.9 vs. 9.9 ± 1.3 (mean difference −1.1, 95 % CI −5.9 to 3.6; p = NS) symptom scores. We conclude that there is no difference in the glucagon, sympathoadrenal, cognitive or symptomatic response during hypoglycaemia induced by either insulin or tolbutamide. This suggests that the different insulin concentrations produced by these contrasting models of hypoglycaemia had no effect on the physiological response and patients taking sulphonylureas can be expected to develop similar warning symptoms to those on insulin.     

Further evidence for a high incidence of nocturnal hypoglycaemia in IDDM: no effect of dose for dose transfer between human and porcine insulins

We tested the hypothesis that transfer from porcine to human insulin causes a fall in nocturnal blood glucose and an increase in the frequency of hypoglycaemic episodes. Twenty IDDM patients (age 19–55, duration 3–36 years) used Velosulin and Insulatard twice daily for 12 weeks, double-blinded to species (human (H) or porcine (P)) in a randomized crossover study. Species was changed after 4 weeks’ run-in and 4 weeks later, with insulin doses unchanged on transfer. Ten patients underwent each sequence (H/P/H or P/H/P) and were admitted on the first and eighth night after transfer for hourly blood glucose measurement (22.00–07.00). Biochemical hypoglycaemia (<3.5 mmol l⁻¹) was observed on 39 of the 80 patient-nights studied (48.75 %). The number of episodes were similar during each night (H1 8, H8 10, P1 10, P8 11, p = 0.83). Total reported symptomatic episodes (H 51 vs P 73, p = 0.85), total HbA₁ (H 9.8 ± 0.3 %, P 10.0 ± 0.3 %, p = 0.32) and daily insulin doses (H 0.63 ± 0.04 units kg⁻¹ day⁻¹ vs P 0.63 ± 0.05 units kg⁻¹ day⁻¹, p = 0.54) were not different. Despite an apparent fall in blood glucose levels from night 1 to 8 on transfer to human (AUC 82.3 ± 7.8 vs 61.4 ± 5.3 mmol.h l⁻¹, p < 0.05) but not porcine insulin (AUC 70.7 ± 7.2 vs 70.1 ± 7.5 mmol.h l⁻¹, p = 0.74), there was no difference when all 4 nights were considered together (p = 0.30). We conclude that dose for dose transfer to human insulin does not increase numbers of episodes of nocturnal or reported hypoglycaemia. © 1997 by John Wiley & Sons, Ltd.     

Beta Cell Response to Oral Glimepiride Administration During and Following a Hyperglycaemic Clamp in NIDDM Patients

The aim of the present study was to assess the beta cell response to glimepiride, administered orally, during and following a hyperglycaemic clamp in 14 NIDDM patients (7 males), aged 62.5 (St. Dev. 7.7) years with a body mass index of 27.3 (2.8) kg m⁻² and HbA_lc of 7.0 (0.7) % at baseline, in a placebo controlled study. All patients were on stable treatment with a second generation sulphonylurea for at least 8 weeks prior to randomization and received placebo (P) or 5 mg glimepiride (G) daily for 7 days and 10 mg prior to a hyperglycaemic clamp (10.9 mmol l⁻¹ for 60 min, preceded by i.v. insulin infusion to stablize fasting blood glucose levels at 4.0 mmol l⁻¹). The clamp was followed by an observation period of 2 h in 5 subjects and 3.5 h in the next 9 subjects, during which blood glucose and plasma insulin, C-peptide and proinsulin levels were measured at regular intervals to determine the effect of glimepiride on the interaction between changes in glycaemia and plasma levels of beta cell products. Neither G nor P elicited a first phase insulin response. Areas under plasma insulin curve during the 1 h hyperglycaemic clamp were 94.2 (39.5) vs 69.1 (26.5) pmol.h l⁻¹ in G and P clamps, respectively (p = 0.002). Total areas (AUC) under the plasma insulin curve were 377 (145) vs 271 (113) pmol.h l⁻¹ in G and P clamps (< 0.05). Total AUCs of C-peptide were 309 (96) and 259 (102 pmol.h.⁻¹, in G and P clamps, respectively, p = 0.01. Total AUCs of proinsulin were 176 (77) versus 119 (56) pmol.h l⁻¹ in G and P clamps, respectively, p = 0.004. Five hours after G and P administration blood glucose levels were 4.7) 92.1) mmol⁻¹ in the G clamp vs 6.2 (1.9) mmol l⁻¹ in the P clamp (p = 0.001). The number of hypoglycaemic events (blood glucose < 3.0 mmol l⁻¹) in the 3.5 h observation period was 3 in G clamps vs 0 in P clamps (p = ns). In conclusion, glimepiride stimulates the second phase insulin and proinsulin secretion. The lowering of blood glucose levels is not accompanied by a commensurate inhibition of the insulin secretion. Further studies are required to compare this new drug with currently available oral hypoglycaemic agents, with respect to glycaemic control and the risk of hypoglycaemia. © 1997 John Wiley & Sons, Ltd.     

UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years

Patients with Type 2 (non-insulin-dependent) diabetes mellitus (DM) on sulphonylurea therapy convert to insulin progressively as the sulphonylureas ‘fail’. The rate of failure and the features of those who fail have been poorly described. To assess secondary failure rates of sulphonylureas, we report on the responses in 1305 patients with newly diagnosed Type 2 DM randomly allocated to therapy with either chlorpropamide or glibenclamide in the UK Prospective Diabetes Study (UKPDS). These patients were initially treated by diet for 3 months and had a fasting plasma glucose >6 mmol l⁻¹; mean age 53 (SD 9) years; BMI 26.8 (SD 5.0) kg m⁻²; and median fasting plasma glucose 9.1 (7.6–12.5 quartiles) mmol l⁻¹. If their fasting plasma glucose subsequently rose above 15.0 mmol l⁻¹, or they developed hyperglycaemic symptoms, additional hypoglycaemic therapy was given: metformin, ultratard insulin, and soluble insulin as required. By 6 years, 44 % had required additional therapy. Of those randomized to glibenclamide, 48 % required additional therapy by 6 years, compared with 40 % of those allocated to chlorpropamide (p < 0.01). 61 %, 39 %, and 23 %, respectively, of patients with fasting plasma glucose ≥10.0 mmol l⁻¹, ≥7.8 mmol l⁻¹ to <10.0 mmol l⁻¹ and <7.8 mmol l⁻¹ at randomization required additional therapy (p < 0.001). In the initial 3 years, non-obese subjects (BMI <30 kg m⁻²) were more likely to require additional therapy than obese patients (BMI ≥30 kg m⁻²) (43 % vs 53 % at 6 years; p < 0.001). Modelled beta-cell function showed that those with lower function were more likely to fail (p < 0.0001). Thus sulphonylureas fail as a therapeutic agent at rates which are dependent both on the phenotype at presentation and perhaps on the agent used initially. Higher failure rates were found in those with higher glucose concentrations, those who were younger, those with lower beta-cell reserve and those randomized to glibenclamide compared with chlorpropamide. © 1998 John Wiley & Sons, Ltd.     

Prandial Glycaemia After a Carbohydrate-rich Meal in Type I Diabetic Patients: Using the Rapid Acting Insulin Analogue [Lys(B28), Pro(B29)] Human Insulin

The time–action profile of the insulin analogue insulin lispro ([Lys(B28), Pro(B29)] human insulin) with its rapid onset and short duration of action might be more suitable to limit hyperglycaemic excursions after a meal rich in rapidly absorbable carbohydrates in comparison to regular human insulin. A randomized, double-blind study was performed in 10 Type I diabetic patients with good metabolic control (HbA_1c 7.0 ± 0.5 %). After a baseline period of 3 h (blood glucose clamped at 6.7 mmol l⁻¹, i.v. insulin infusion of 0.2 mU kg⁻¹ min⁻¹ throughout the study), the patients ate a pizza, drank a cola and had a carbohydrate-rich dessert (total carbohydrate content 140 g). Immediately before the meal 15.4 ± 3.5 U of either insulin preparation were injected subcutaneously. Blood glucose concentrations were monitored continuously thereafter. Following the injection of insulin lispro the area under the blood glucose curve after the meal was 78 % of that of regular insulin (1.76 ± 0.34 vs 2.26 ± 0.68 mol l⁻¹ *240 min⁻¹; p < 0.01). Maximal blood glucose excursions were higher and were reached later after regular insulin as compared to insulin lispro (11.9 ± 2.8 vs 9.9 ± 1.4 mmol l⁻¹; p < 0.05; 66 ± 37 vs 41 ± 7 min; p < 0.05). Maximal individual differences in the blood glucose excursions (regular human insulin minus insulin lispro) were 4.8 ± 2.2 mmol l⁻¹ (p < 0.0001 against zero) after 110 ± 37 min. In Type I diabetic patients prandial blood glucose excursions after a carbohydrate rich meal were reduced after preprandial injection of insulin lispro in comparison to human regular insulin.     

The Short Insulin Tolerance Test: Feasibility Study Using Venous Sampling

The short insulin tolerance test (ITT) is both a simple and valid method of quantifying insulin sensitivity although arterialization of samples and the risk of hypoglycaemia remain as potential difficulties. We examined the safety and reproducibility of using venous sampling with insulin doses of 0.1U kg⁻¹ and 0.05 U kg⁻¹ in healthy subjects. Whole blood glucose concentrations were measured contemporaneously and the rate of plasma glucose decline (mmol l⁻¹ min⁻¹) for each test was estimated from unlogged venous plasma glucose concentrations measured at 1 min intervals. The mean rates of plasma glucose decline for the 0.1 U kg⁻¹ and 0.05 U kg⁻¹ insulin doses were 0.26 mmol l⁻¹ min⁻¹ (n = 11, range = 0.17–0.41, intrasubject coefficient of variation (CV) = 9.4%) and 0.25 mmol l⁻¹ min⁻¹ (n = 6, range 0.19–0.46, intrasubject CV = 15.9%), respectively. Reversal of significant hypoglycaemia was necessary in one subject before 15 min post-insulin. We found that: (1) venous sampling provides a reproducible measure of glucose uptake after insulin, (2) contemporaneous bedside glucose sampling identifies those at risk of significant hypoglycaemia during the ITT, and (3) the 0.1 U kg⁻¹ dose response is more reproducible and no less safe than the half dose response. We conclude that the current ITT protocol would be made safer and simpler with the above modifications although further studies comparing venous with arterialized sampling are needed.     

Insulin Secretion and Sensitivity in Women Fulfilling WHO Criteria for Gestational Diabetes

Abnormalities of insulin secretion rather than insulin sensitivity are described in women fulfilling the American criteria for gestational diabetes. We examined insulin secretion and insulin sensitivity in 38 women at risk of gestational diabetes categorized according to the less stringent WHO criteria, based on the 75 g oral glucose tolerance test, performed at 24 weeks gestation. Insulin sensitivity was assessed at 28 and 36 weeks using the short insulin tolerance test. Applying WHO criteria, 18 women had GDM. Age and body mass index of the GDM and glucose tolerant women were similar (32.4 ± 1.1 (SE) vs 32.3 ± 1.9 yr; 28.7 ± 1.5 vs 28.8 ± 1.7 kg m^-2, respectively). Fasting glucose was higher in the GDM women than controls (5.1 ± 0.2 vs 4.5 ± 0.1 mmol l^-1, p<0.025) while fasting insulin was similar (75 ± 18 vs 90 ± 16 pmol l^-1). The 30-min insulin concentration during the OGTT was lower in the GDM women than controls (436 ± 61 vs 788 ± 152 pmol l^-1, p< 0.05), while the insulin sensitivity at 28 (87 ± 5 vs 76 ± 5 μmol l^-1 min) and 36 weeks (73 ± 8 vs 76 ± 8 μmol l^-1 min) was similar. A negative correlation existed between the 30-min insulin and 120-min glucose concentration during the OGTT (Rho -0.328, p<0.05). The WHO criteria for GDM identify women with similar abnormalities of insulin secretion as the more stringent American criteria.     

Diet Treatment of Newly Presenting Type 2 Diabetes Improves Insulin Secretory Capacity,but Has No Effect on Insulin Sensitivity

Fifteen newly diagnosed obese Type 2 diabetic subjects were treated with diet alone for 3 months with a median 1.5 kg weight loss. Each had a Continuous Infusion of Glucose with Model Assessment (CIGMA) test, at diagnosis and at 3 months, measuring insulin and C-peptide responses, and deriving mathematically modelled measures of beta-cell function and insulin sensitivity. Median fasting glucoses were 9.6 mmol l^?1 at diagnosis and 8.5 mmol l^?1 at 3 months (NS). Median fasting insulin was 9.3 mU l^?1 at diagnosis and 11.7 mU l^?1 at 3 months (NS). Median fasting C-peptide was 0.58 nmol l^?1 at diagnosis and 0.64 nmol l^?1 at 3 months (p < 0.05). Median achieved plasma insulin increased from 13.8 mU l^?1 at diagnosis to 17 mU l^?1 at 3 months (p < 0.02); median achieved plasma C-peptide increased from 0.72 nmol l^?1 at diagnosis to 0.81 nmol l^?1 at 3 months (p < 0.002). Modelled beta-cell function rose from median 26 % at diagnosis to 37 % at 3 months (p < 0.02). Modelled insulin sensitivity showed no significant change (median 0.31 at diagnosis, 0.27 at 3 months, NS). Elevation of achieved C-peptide was positively correlated with weight loss (R_s = 0.53, p < 0.05), but not with change in fasting glucose. Diet treatment of newly diagnosed Type 2 diabetes, with modest weight loss, results primarily in improvement of insulin secretory capacity, rather than insulin sensitivity.     

Effect of Combination Therapy of Troglitazone and Sulphonylureas in Patients with Type 2 Diabetes Who Were Poorly Controlled by Sulphonylurea Therapy Alone

The clinical efficacy of troglitazone, a new oral hypoglycaemic agent was investigated in Type 2 diabetes in combination with sulphonylureas. Two hundred and ninety-one patients with Type 2 diabetes (age 21–81 years) whose previous glycaemic control by sulphonylureas was judged stable but unsatisfactory (fasting plasma glucose (FPG) > 8.3 mmol l⁻¹) were randomly allocated into the troglitazone treatment group (troglitazone group, n = 145) or the placebo treatment group (placebo group, n = 146). They were treated by test drugs for 12 weeks in combination with the same dose of sulphonylureas before the trial. One hundred and twenty-two patients who received troglitazone and 126 patients who received placebo were evaluated for efficacy. The baseline characteristics did not differ significantly between the two groups. In the troglitazone group, FPG and HbA_1C decreased significantly after the treatment (before vs after, FPG: 10.8 ± 2.0 mmol l⁻¹ vs 9.2 ± 2.5 mmol l⁻¹, p < 0.001; HbA_1C: 9.2 ± 1.4 % vs 8.5 ± 1.5 %, p < 0.001). FPG and HbA_1C did not change after the treatment in the placebo group (before vs after, FPG: 10.5 ± 1.7 mmol l⁻¹ vs 10.7 ± 2.2 mmol l⁻¹; HbA_1C: 9.0 ± 1.5 % vs 9.2 ± 1.6 %). Serum total cholesterol and HDL-cholesterol did not change in either group, however, serum triglyceride significantly decreased in the troglitazone group. No serious adverse events occurred in either group. In conclusion, troglitazone 400 mg day⁻¹ had a significant hypoglycaemic effect in combination with sulphonylureas without any serious adverse events. Troglitazone, developed as an insulin action enhancer, can be a useful hypoglycaemic agent in the treatment of patients with Type 2 diabetes who are not well controlled by sulphonylureas alone.     

Long-term administration of theophylline and glucose recovery after hypoglycaemia in patients with Type 1 diabetes mellitus

The methylxanthine theophylline increases intrahepatic c-AMP and c-AMP mediates the hepatic glucose response to adrenaline and glucagon. Intravenous theophylline increases glucose recovery during acute insulin-induced hypoglycaemia and caffeine increases hypoglycaemia awareness and glucoregulatory hormone secretion. In this study we tested the hypothesis that long-term administration of theophylline might augment glucose recovery after insulin-induced hypoglycaemia. Eleven healthy subjects and 8 patients with Type 1 diabetes mellitus were made hypoglycaemic by 60 min insulin infusion (40 mU m⁻²) after 2 weeks’ oral therapy with Euphyllin Retard (theophylline) or placebo. Plasma glucose nadir was 2.54 (2.31–2.77) mmol l⁻¹ after Euphyllin Retard and 2.27 (2.05–2.48) mmol l⁻¹ after placebo (mean difference 0.26 (0.05–0.58) mmol l⁻¹, p = 0.09) for healthy control subjects and 2.56 (2.07–3.04) mmol l⁻¹ and 2.19 (1.37–2.65) mmol l⁻¹ (mean difference 0.38 (0.12–0.63) mmol l⁻¹, p = 0.01), respectively, for diabetic patients. The area under the glucose curve was greater after theophylline treatment for healthy control subjects (p = 0.0292) and for diabetic patients (p = 0.0241) but there were no concomitant significant increases in plasma c-AMP or in endogenous glucose production rate. Whether the increase in glucose recovery is large enough to suggest that chronic theophylline administration will protect against insulin-induced hypoglycaemia remains unsettled. © 1998 John Wiley & Sons, Ltd.     

Reduced adipocyte insulin sensitivity in Caucasian and Asian subjects with coronary heart disease

The association between insulin resistance and coronary heart disease (CHD) is strong in the British Indian-Asian population. Adipocyte metabolism may contribute to both insulin resistance and CHD. We examined insulin-stimulated glucose uptake in adipocytes and in vivo insulin sensitivity using the fasting insulin resistance index (FIRI) in 60 subjects (45 Caucasian and 15 Asian) with CHD and 30 Caucasian subjects without CHD. In 25 CHD subjects (18 Caucasian and 7 Asian), the relationship between adipocyte insulin sensitivity and non-esterified fatty acid (NEFA) suppression to oral glucose was examined. Compared with controls, the CHD subjects had higher values of fasting insulin [51 (46 to 54) pmol l⁻¹ vs 36 (31 to 41) pmol l⁻¹ p < 0.01] and FIRI [1.65 (1.5 to 1.79) vs 1.06 (0.89 to 1.23), p < 0.01]. Among the CHD subjects, the Asians had higher values than Caucasian [insulin 58 (48 to 67) pmol l⁻¹ vs 48 (44 to 53) pmol l⁻¹ p < 0.01, FIRI 1.89 (1.44 to 2.13) vs 1.62 (1.4 to 1.79), p < 0.01)]. Insulin-stimulated glucose uptake in adipocytes was lower in the CHD than control subjects [56 (50 to 62) vs 115 (75 to 132) attomol min⁻¹.mm², p < 0.05], being most reduced among the Asians. It was positively correlated with postprandial NEFA suppression and negatively with insulin release. In conclusion, abnormalities of adipocyte function and insulin sensitivity occur in CHD and may contribute to its aetiology. Copyright © 1998 John Wiley & Sons, Ltd.     

Insulin resistant subjects lack islet adaptation to short-term dexamethasone-induced reduction in insulin sensitivity

Aims/hypothesis. To establish whether islet compensation to deterioration of insulin action depends on inherent insulin sensitivity. Methods. We examined insulin and glucagon secretion after iv arginine (5 g) at fasting, 14 and greater than 25 mmol/l glucose concentrations before and after lowering of insulin sensitivity by oral dexamethasone (3 mg twice daily for 2 1/2 days) in 10 women with normal glucose tolerance, aged 58 or 59 years. Five women had high insulin sensitivity as shown by euglycaemic, hyperinsulinaemic clamp (99 ± 12 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1; means ± SD) whereas five women had low insulin sensitivity (34 ± 15 nmol glucose · kg body weight^–1· min^–1/pmol insulin · l^–1). Results. Dexamethasone reduced insulin sensitivity in both groups. Fasting insulin concentration increased by dexamethasone in high insulin sensitivity (72 ± 10 vs 49 ± 9 pmol/l, p = 0.043) but not in low insulin sensitivity (148 ± 63 vs 145 ± 78 pmol/l) whereas the fasting glucose concentration increased in low insulin sensitivity (6.5 ± 0.8 vs 5.8 ± 0.6 mmol/l, p = 0.043) but not in high insulin sensitivity (5.3 ± 0.8 vs 5.3 ± 0.6 mmol/l). Fasting glucagon concentration was not changed. Plasma insulin concentrations after raising glucose to 14 and more than 25 mmol/l and the insulin response to arginine at more than 25 mmol/l glucose were increased by dexamethasone in high insulin sensitivity (p < 0.05) but not changed by dexamethasone in low insulin sensitivity. Furthermore, in high but not in low insulin sensitivity, dexamethasone reduced the glucagon response to arginine (p = 0.043). Conclusion/interpretation. The results show that adaptation in islets function to dexamethasone-induced short-term reduction in insulin sensitivity is lacking in subjects with low inherent insulin sensitivity. [Diabetologia (1999) 42: 936–943] Received: 26 January 1999 and in revised form: 1 March 1999     

Serum Lipoprotein Levels and Plasma Concentrations of Insulin,Intact and 32, 33 Split Proinsulin in Normoglycaemic Relatives of Patients with Type 2 Diabetes

Type 2 diabetes is associated with abnormal lipoprotein levels and altered plasma concentrations of insulin, intact and 32, 33 split proinsulin. To investigate whether these are early features of the disease, we studied 36 normoglycaemic first-degree relatives of patients with Type 2 diabetes (13 European, 15 of Asian (Indian-subcontinent), and 8 of Afro-Caribbean origin) and 36 control subjects with no family history of diabetes. Relatives and controls were matched for age (mean ± S.E. 33 ± 2 vs 34 ± 2 years), body mass index (23.7 ± 0.5 vs 23.7 ± 0.6 kg m^?2), sex (17 M, 19 F) and ethnic origin. After an overnight fast, blood was sampled for measurement of serum lipids, plasma glucose and insulin, intact and 32, 33 split proinsulin by specific immunoradiometric assays. Relatives and controls had similar fasting concentrations of glucose (5.0 ± 0.1 vs 4.9 ± 0.1 mmol l^?1), total cholesterol (4.51 ±0.13 vs 4.54 ± 0.17 mmol l^?1), HDL-cholesterol (1.21 ± 0.06 vs 1.10 ± 0.05 mmol l^?1), LDL-cholesterol (2.84 ± 0.14 vs 2.96 ± 0.14 mmol l^?1) and triglyceride (median (range) 0.78 (0.44–2.45) vs 0.83 (0.41–4.03) mmol l^?1). Fasting levels of insulin (50.4 (18.9–174.0) vs 51.6 (10.0–118.0) pmol l^?1 intact proinsulin (2.8 (0.1–15.0) vs 2.1 (0.6–6.4) pmol l^?1 and 32, 33 split proinsulin (2.0(0–23.7) vs 1.6 (0.3–6.0) pmol l^?1) were not significantly different between relatives and controls. Analysis of results for each ethnic group separately did not alter the findings. It is concluded that glucose-tolerant subjects at risk of future diabetes have normal fasting lipid concentrations and plasma levels of insulin and its precursors. This suggests that the dyslipidaemia and altered insulin concentrations found in overt Type 2 diabetes are not present before the onset of glucose intolerance.     

Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM

Summary Insulin is known to increase expression of the ob gene product leptin in adipose tissue of rodents. We determined whether insulin increases circulating leptin concentrations in humans, and whether this effect might be altered in patients with non-insulin-dependent diabetes mellitus (NIDDM). Plasma leptin concentrations were determined during an 8.5-h hyperinsulinaemic clamp (serum free insulin approximately 480 pmol/l) and during an 8.5-h infusion of physiological NaCl solution (saline) in eight normal subjects (age 51±3 years, BMI 26.3±0.6 kg/ m², fasting plasma glucose 5.6±0.2 mmol/l) and seven patients with NIDDM (age 54±2 years, 27.0±0.9 kg/m², 11.1±0.8 mmol/l). Fasting serum insulin level correlated with plasma leptin (r=0.72, p<0.005), even after adjusting for the percentage of body fat (p<0.005). During the insulin infusion, a significant increase in the plasma leptin concentration was observed after 6 h (37±14%; 5.2±0.8 vs 3.9±0.6 ng/ml, 6 vs 0 h, p<0.05) in the normal subjects and after 8.5 h (38±11%; 7.1±1.0 vs 5.5±0.9 ng/ml, 8.5 vs 0 h, p<0.05) in the patients with NIDDM. During the saline infusion, plasma leptin concentrations decreased significantly in the normal subjects by 11±1% (p<0.005) and in the patients with NIDDM by 14±1% (p<0.01) after 2 h. During the infusion of insulin as compared to saline, plasma leptin concentrations were 32±13 (p<0.05), 53±14 (p<0.001), 106±15 (p<0.001) and 165±21 (p<0.001)% higher at 2, 4, 6 and 8.5 h in the normal subjects, and 11±9 (p<0.05), 27±10 (p<0.05), 58±7 (p<0.001) and 106±13 (p<0.001)% higher in the patients with NIDDM, respectively. No differences were observed in plasma leptin concentrations between the normal subjects and patients with NIDDM, under any conditions. We conclude that prolonged exposure to insulin increases plasma leptin concentrations in humans implying a role for insulin in chronic but not acute regulation of plasma leptin concentrations. The decrease in plasma leptin concentrations during saline infusion was greater than that expected on the basis of change in serum insulin concentrations, suggesting that factors other than insulin also contribute to regulation of plasma leptin concentrations.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus     

Effect of Metformin on Intact Proinsulin and des 31,32 Proinsulin Concentrations in Subjects with Non-insulin-dependent (Type 2) Diabetes Mellitus

We have investigated the effects of metformin treatment on concentrations of proinsulin-like molecules in subjects with Type 2 (non-insulin-dependent) diabetes mellitus. Metformin was given for 12 weeks in an increasing dose up to 850 mg three times daily in a double-blind placebo-controlled cross-over design to 27 subjects (age 53.0 ± 9.9 years; 19 male, 8 female). Concentrations of insulin and proinsulin-like molecules were measured by highly specific enzymoimmunometric assays. The end of metformin treatment was compared with end of placebo treatment. Metformin lowered fasting plasma glucose concentrations (at 12 weeks, metformin: 8.0 ± 2.5 vs placebo: 12.0 ± 2.3 mmol l⁻¹, p r2 0.001;). Concentrations of intact (median change −2.9 (range −28.4 to +2.5 pmol l⁻¹), p =0.02) and des 31,32 proinsulin (median change −1.6 (range −14.1 to +5.4 pmol l⁻¹), p = 0.07) and percentage of proinsulin-like molecules were reduced by metformin treatment (median change −6 % (range −16 % to +6 %), p = 0.02). Changes in the ratio of proinsulin-like molecules were significantly related with those in fasting plasma glucose (r_s = 0.69, p < 0.001). Changes in concentrations of intact and des 31,32 proinsulin on metformin were not related to changes in body mass index or fasting glucose concentration or changes in concentrations of total triglyceride, cholesterol, and plasminogen activator inhibitor-1. Therefore, metformin treatment in subjects with Type 2 diabetes mellitus significantly reduced concentrations of proinsulin-like molecules over a 12-week period. However, these changes were not related to changes in cardiovascular risk factors seen during metformin treatment. We conclude that short-term effects of metformin treatment on proinsulin-like molecules are similar to those previously observed with dietary treatment in subjects with Type 2 diabetes but opposite to those of sulphonylurea treatment. The effect of long-term treatment with metformin on proinsulin-like molecules needs to be assessed.