The influence of improved glycaemic control with insulin and sulphonylureas on acute phase and endothelial markers in Type II diabetic subjects.

AIMS/HYPOTHESIS: Improved glycaemic control might reduce both microvascular and macrovascular complications of Type II diabetes (non-insulin-dependent) mellitus. To explore such possible mechanisms, we investigated the effects of intensive treatment on markers of endothelial dysfunction and of acute phase activation, using both sulphonylureas and insulin. METHODS: In a randomised cross-over study we gave sulphonylureas or insulin each for a period of 16 weeks to 22 poorly controlled Type II diabetic subjects who were being treated by diet. There was a 4 week washout period between each treatment. Subjects were studied at baseline and at the end of each treatment. RESULTS: Treatment with sulphonylureas and insulin resulted in similar improvements in glycaemic control (glycated haemoglobin, baseline: 11.8 [(SD 2.2)%; after sulphonylureas: 8.6 (1.2)%,p < 0.001; after insulin: 8.6 (1.2)%, p < 0.001] and in insulin sensitivity ¿metabolic clearance rate of glucose, baseline: median 1.75 [interquartile (IQ) range 1.41, 2.27] ml x kg(-1) x min(-1); after sulphonylureas: 2.41 (1.82, 3.01) ml x kg(-1) x min(-1), p = 0.001; after insulin: 2.23 (1.92, 2.75) ml x kg(-1) min(-1), p = 0.027¿. There were no significant changes in concentrations of endothelial markers von Willebrand factor, cellular fibronectin, thrombomodulin, tissue plasminogen activator, soluble E-selectin or soluble intercellular adhesion molecule-1 or in urinary albumin excretion rate after either treatment period. Concentrations of C-reactive protein were not significantly influenced by sulphonylureas but fell after insulin [baseline: median 4.50 (IQ range 1.37, 6.44) microg x ml(-1); sulphonylureas: 2.69 (0.88, 9.65) microg x ml(-1) (p = 0.53); insulin: 2.07 (1.16, 5.24) microg x ml(-1) (p = 0.017)]. There were, however, no significant effects of either treatment on circulating concentrations of fibrinogen (p = 0.28-0.34) or of the proinflammatory cytokines interleukin-6 or tumour necrosis factor-alpha (p = 0.65-0.79). CONCLUSION/INTERPRETATION: Markers of endothelial dysfunction and concentrations of proinflammatory cytokines in Type II diabetes are not influenced by improved glycaemic control over 16 weeks. Improved metabolic control with insulin could, however, be associated with reduced concentrations of the acute phase marker C-reactive protein.

Effect of salt-loading on blood pressure, insulin sensitivity and limb blood flow in normal subjects.

1. The aim of this study was to determine the effects of high (220 mmol/day) and low (40 mmol/day) salt intake for 6 days on blood pressure, leg blood flow and insulin sensitivity in 18 healthy normotensive subjects. 2. Twenty-four-hour ambulatory blood pressure was measured at baseline, during salt-loading and salt-depletion. Insulin sensitivity was determined by a two-step euglycaemic-hyperinsulinaemic clamp (low and high insulin infusion rates: 40 and 600 m-unit.min-1.m-2 respectively) and leg blood flow by plethysmography. 3. Salt-loading resulted in changes in weight [change between salt-loading and salt-restriction: delta=+0.45 (S.D. +/-0.69) kg, P=0.015], plasma renin [delta=-11.5 (S.D.+/-12.9) micro-units/l, P=0.001] and urinary noradrenaline [delta=-8.6 (S.D. +/-18.7) nmol/mmol creatinine, P=0.05]. There were borderline significant increases in 24-h systolic blood pressure [delta=+5.8 (S. D.+/-14.2) mmHg, P=0.06] and plasma volume [delta=+0.29 (S.D.+/-0. 67) litres, P=0.08]. 4. Insulin sensitivity was similar in both salt states. Geometric mean metabolic clearance rate of low-dose insulin: low salt, 5.13 (S.D.x//1.35) dl/min; high salt, 4.94 (S.D.x//1.37) dl/min, P=1.0. Geometric mean metabolic clearance rate of high-dose insulin: low salt, 9.68 dl/min (S.D.x//1.30); high salt, 9.68 (S.D. x//1.27) dl/min, P=0.69. 5. Leg blood flow response to high-dose insulin on high salt increased significantly compared with low salt. Percentage change of blood flow on low salt, delta=+36.6 (S.D.+/-22. 9)% versus high salt, delta=+66.8 (S.D.+/-52.2)%, P=0.03. 6. There were no significant relationships between salt-related changes in limb blood flow and changes in insulin sensitivity at either insulin infusion rate. 7. We conclude that salt-loading, despite changing body weight, the renin-angiotensin-aldosterone system, urinary noradrenaline and the leg blood flow response to insulin, has no significant effect on insulin sensitivity. Salt-loading causes dissociated effects on insulin-induced vasodilatation and glucose disposal.

Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes.

In non-insulin-dependent diabetes mellitus (NIDDM), cardiovascular risk factors improve during treatment, but whether insulin (I) differs from sulfonylurea (SU) therapy is unclear. To separate the contributions of improved diabetic control versus treatment regimen to risk factors, we examined the effects of SU and I on insulin sensitivity, basal and post-glucose load levels of insulin-like molecules, fibrinolysis, and lipid concentrations. Twenty poorly controlled, diet-treated NIDDM subjects were given I or SU each for a period of 16 weeks in a randomized crossover study, with a 4-week washout period between each treatment. Subjects were studied at the baselines (B1 and B2) and after each treatment. Treatment with I or SU produced similar improvements in glycemia (hemoglobin A1 [HbA1] B1, 11.7% +/- 2.1%; SU, 8.5% +/- 0.9%; I, 8.6% +/- 1.2%) and the metabolic clearance rate of glucose ([MCR-G] B1, 1.86 x/divided by 1.4; SU, 2.36 x/divided by 1.4 (P = .005 vB1); I, 2.27 x/divided by 1.4 (P = .07 vB1) ml x kg(-1) x min(-1)). On SU therapy, subjects had higher fasting and post-glucose load levels of intact proinsulin compared with B1 and I (fasting, 13.9 x/divided by 2.6 v 9.5 x/divided by 2.2 (P = .004) and 9.1 x/divided by 2.4 pmol x L(-1) (P = .01), respectively). Plasminogen activator inhibitor-1 (PAI-1) activity and antigen were higher than at B1 on SU therapy (23.7 v 19.9 AU x mL(-1) (P = .02) and 47.6 v 32.2 ng x mL(-1) (P = .006), respectively), but not on I. There were no changes compared with B1 and no differences between the two therapies in total, very-low-density lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) cholesterol and triglyceride, low-density lipoprotein (LDL), high-density lipoprotein 2 (HDL2) and HDL3 cholesterol, apolipoprotein (apo) A1, A2, and B1, or lipoprotein (a) [Lp(a)] levels. In conclusion, (1) treatment with SU or I resulted in equal improvement in glycemia and insulin sensitivity, (2) intact proinsulin and PAI-1 antigen and activity were higher on SU, and (3) there were no differences in lipid concentrations with improved glycemia or between therapies.

Effects of Glimepiride vs Glibenclamide on Ischaemic Heart Disease Risk Factors and Glycaemic Control in Patients with Type 2 Diabetes Mellitus.

OBJECTIVE: This study aimed to compare the effects of glimepiride and glibenclamide on glycaemic control and a range of risk factors for ischaemic heart disease (IHD), including concentrations of insulin-like molecules. PATIENTS: A double-blind, placebo-controlled, randomised, crossover comparison of 4 weeks of treatment with glibenclamide 2.5 to 20 mg/day and glimepiride 1 to 8 mg/day was undertaken in 29 type 2 (non-insulin-dependent) diabetic patients. The average (mean +/- SD) duration of diabetes was 8.5 (+/- 5.9) years. RESULTS: Compared with placebo, fasting plasma glucose was significantly lower on both drugs [placebo (P): mean (SD) 11.9 (3.3) mmol/L, glibenclamide: 9.5 (3.2); p < 0.0005, glimepiride: 10.6 (3.4); p = 0.01] and lower on glibenclamide than glimepiride (p = 0.003). The integrated, meal-stimulated rise in glucose was lower with glimepiride, but not glibenclamide, compared with placebo [P: 588.1 (372.2) mmol/L.min, glimepiride: 443.0 (346.9) mmol/L.min; p = 0.010, glibenclamide: 586.4 (366.2) mmol/L.min; p = 0.630]. There was no between-drug difference (p = 0.145). Fasting insulin did not differ compared with placebo [P: 92.3 (61.3) pmol/L, glimepiride: 91.8 (60.6) pmol/L; p = 0.787, glibenclamide: 87.8 (51.6) pmol/L; p = 0.379] and there was no between-drug difference (p = 0.601). There were no significant differences in effect upon fasting concentrations of C-peptide, proinsulin, des 31,32 proinsulin or the ratio of proinsulin-like to total insulin-like molecules. The integrated insulin and C-peptide responses to a meal were significantly greater on both drugs than on placebo [insulin: median (25th, 75th percentile), P: 7073 (2430-18296) pmol/L.min, glibenclamide: 18045 (4290-35850) pmol/L.min; p = 0.0005, glimepiride: 14355 (5880-32820) pmol/L.min; p = 0.0001; C-peptide mean (SD): P: 51.89 (49.01) nmol/L.min, glibenclamide: 90.15 (59.44) nmol/L.min; p = 0.006, glimepiride: 89.75 (61.78) nmol/L.min; p = 0.007], but there was no between-drug difference [integrated insulin (p = 0.923), integrated C-peptide (p = 0.680)]. Compared with placebo, plasminogen activator inhibitor (PAI) antigen was significantly lower on glibenclamide but not glimepiride [P: 28.8 (19.7) microg/L, glimepiride: 24.4 (15.2) microg/L; p = 0.300, glibenclamide: 20.0 (10.9) microg/L; p = 0.003]. PAI activity was similar with all agents, as was low density lipoprotein (LDL)-cholesterol [P: 4.4 (1.2) mmol/L, glimepiride: 4.2 (0.9) mmol/L; p = 0.225, glibenclamide: 4.5 (1.4) mmol/L; p = 0.174]. Corrected for fasting plasma glucose, LDL was 0.5 mmol/L lower on glimepiride than on glibenclamide (95% confidence interval: -0.8, -0.2), a clinically significant difference. There were no significant differences in other measured factors. CONCLUSION: Both drugs improved glycaemia without adversely affecting a range of IHD risk factors.

The relationship of concentrations of insulin and proinsulin-like molecules with coronary heart disease prevalence and incidence. A study of two ethnic groups.

OBJECTIVE: To define the potential role of proinsulin-like molecules as risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS: Fasting concentrations of proinsulin, des-31,32-proinsulin, and insulin, and of insulin 2 h after a 75-g glucose load, were measured in 1,034 nondiabetic europid subjects and 257 south Asian subjects and related to prevalent coronary heart disease (Minnesota-coded electrocardiographic criteria or ischemic chest pain). In 137 south Asian subjects, the fasting concentrations were related to incident coronary heart disease over a 6.5-year follow-up. RESULTS: The standardized odds ratios for prevalent coronary heart disease were as follows: fasting insulin, 1.29 (1.11-1.49), P = 0.0006; 2-h insulin, 1.25 (1.08-1.45), P = 0.003; proinsulin, 1.23 (0.99-1.53), P = 0.058; and des-31,32-proinsulin, 1.32 (1.03-1.69), P = 0.026. The odds ratios were similar in the two ethnic groups. These relationships became insignificant when controlling for age, sex, and BMI. The standardized odds ratios for incident coronary heart disease were as follows: fasting insulin, 0.99 (0.63-1.55), P = 0.97; proinsulin, 1.13 (0.72-1.78), P = 0.59; and des-31,32-proinsulin, 1.00 (0.61-1.63), P = 1.00. CONCLUSIONS: We have found similar relationships between concentrations of proinsulin-like molecules and prevalent coronary heart disease, as are observed for insulin in these nondiabetic subjects, although these molecules comprise only approximately 10% of all insulin-like molecules. It appears biologically implausible that these relationships represent cause and effect.

Glucose intolerance in thalassemia major is related to insulin resistance and hepatic dysfunction.

Glucose intolerance is a common consequence of transfusion therapy in patients with thalassemia major (TM), but the relative contribution of pancreatic damage and insulin resistance to glucose intolerance is unclear. We have investigated oral (OGTT) and intravenous (IVGTT) glucose tolerance, insulin sensitivity, and fasting concentrations of insulin, proinsulin, and des 31,32 proinsulin in 12 patients with TM (seven hepatitis C virus [HCV] antibody-negative and five-positive), eight patients with hepatic cirrhosis, and nine healthy controls. Two-hour plasma glucose concentrations were marginally higher in anti-HCV-negative (median, 7.4 mmol/ L; range, 4.0 to 8.2) and significantly so in anti-HCV-positive thalassemics (median, 8.5 mmol/L; range, 6.4 to to 23.0) and cirrhotics (median, 8.0 mmol/L; range, 4.7 to 17.6) than in controls (median, 5.5 mmol/L; range, 3.0 to 6.3). Insulin sensitivity was also reduced in the three patient groups (P < .05). Insulin resistance was the main determinant of oral glucose intolerance in all patient groups (partial r2 = .49, P < .0001, n = 28). In turn, the main determinants of insulin insensitivity in TM patients were liver damage (albumin, r = .67, P = .02) and serum ferritin concentration (r = -.62, P = .03). There was no relationship of either 2-hour or incremental insulin concentrations with ferritin levels or with HCV status in TM subjects. Moreover, these patients showed no elevation of concentrations of proinsulin and des 31,32 proinsulin, markers of pancreatic beta-cell damage, in excess of those observed in cirrhotic patients. In conclusion, the glucose intolerance of TM, like that of cirrhosis, is associated with insulin resistance, not insulin deficiency, and may be a direct or indirect consequence of hepatic damage.

Insulin resistance in non-insulin-dependent diabetes mellitus is associated with microalbuminuria independently of ambulatory blood pressure.

Microalbuminuria in both insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) is a marker for insulin resistance. Microalbuminuria is also associated with hypertension, itself an insulin-resistant state. Therefore, in order to examine the independent relationships of microalbuminuria with blood pressure and insulin resistance, we measured ambulatory blood pressure (Takeda TM-2420), insulin resistance (modified Harano method), and urinary albumin excretion rate (overnight urine collection) in 36 subjects with NIDDM. Albumin excretion correlated with 24-h systolic blood pressure (r = 0.49, p = 0.003), and insulin sensitivity (r = -0.39, p = 0.007). Microalbuminuric subjects had reduced insulin sensitivity compared with normoalbuminuric subjects [Mean (SD) 2.95 (0.33) versus 4.67 (0.56) ml.kg-1.min-1; p = 0.013]. In multivariate analysis including ambulatory blood pressure and insulin resistance, urinary albumin excretion was associated primarily with insulin resistance, with smaller contributions from glycated hemoglobin and male gender. These data suggest that microalbuminuria in NIDDM, although associated with hypertension, is also independently associated with insulin resistance.

Insulin resistance and not hyperinsulinaemia determines erythrocyte Na+/Li+ countertransport in non-insulin-dependent diabetes mellitus.

Insulin resistance and increased erythrocyte Na+/Li+ countertransport activity are well documented in subjects with essential hypertension, raising the question whether compensatory hyperinsulinaemia might be responsible for activating Na+/Li+ countertransport. We measured Na+/Li+ countertransport in 63 non-nephropathic non-insulin-dependent diabetic subjects (36 hypertensive, 27 normotensive), finding no correlation with fasting levels of insulin (r = 0.074, P = 0.28), despite using a sensitive and specific insulin assay. In contrast, in 33 of the subjects in whom insulin sensitivity was measured, Na+/Li+ countertransport correlated significantly with the whole body glucose clearance rate (r = -0.37, P = 0.036). It is concluded that increased Na+/Li+ countertransport may be a cellular marker for insulin resistance, but that hyperinsulinaemia is not likely to be the factor which mediates this relation.

The relationship of urinary albumin excretion rate to ambulatory blood pressure and erythrocyte sodium-lithium countertransport in NIDDM.

Increased erythrocyte sodium-lithium countertransport rate is found in non-diabetic subjects with essential hypertension, and in insulin-dependent diabetic subjects with nephropathy. However, relationships between these variables in non-insulin-dependent diabetic subjects are ill-defined. In order to characterise the relationships between blood pressure, urinary albumin excretion, and erythrocyte sodium-lithium countertransport, 66 subjects with non-insulin-dependent diabetes were studied. Urinary albumin excretion rate correlated with mean 24-h ambulatory systolic blood pressure (r = 0.57; p < 0.001), but not with sodium-lithium countertransport (r = 0.06; p = 0.31). No significant relationship was observed between 24-h systolic blood pressure and erythrocyte sodium-lithium countertransport (r = 0.16; p = 0.17). The principal differences between microalbuminuric and normoalbuminuric subjects (albumin excretion rate > 15 micrograms.min-1 [n = 20], and < 15 micrograms.min-1, [n = 46]) were: higher 24-h systolic blood pressure (145.9 [16.8] mmHg vs 131.9 [16.8] mmHg; p = 0.006), nocturnal heart rate (72.4 [8.9] vs 67.4 [8.9] beats.min-1; p = 0.042), and HbA1 (11.3 [1.5]% vs 10.1 [2.0]%; p = 0.028), and a longer median duration of diabetes (10.0 vs 5.0 years; p = 0.02). In contrast, there was no significant difference in sodium-lithium countertransport rate between microalbuminuric (0.41 [0.18] mmol.l-1.h-1) and normoalbuminuric subjects (0.39 [0.15] mmol.l-1.h-1; p = 0.687).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance, insulin, proinsulin, and ambulatory blood pressure in type II diabetes.

Both insulin resistance and insulin concentrations correlate with blood pressure in nondiabetic subjects, but there is no consensus on these relations in subjects with non-insulin-dependent diabetes, perhaps because of the use of nonspecific insulin assays and clinic blood pressure measurement. Therefore, we have investigated the relation between ambulatory blood pressure, insulin sensitivity (measured by an insulin sensitivity test), and levels of insulin and its principal precursors, measured by specific assays, in 24 subjects with non-insulin-dependent diabetes. Insulin sensitivity (glucose metabolic clearance rate) correlated strongly with mean 24-hour ambulatory systolic blood pressure (r = -.650, P < .001). In contrast, there was no relation between this blood pressure index and fasting levels of insulin (r = .096, P = NS) or all insulin-like molecules (r = .077, P = NS). Dichotomized on 24-hour ambulatory systolic blood pressure levels, the hypertensive group was more insulin resistant than the normotensive group (metabolic clearance rate, 3.6 [0.7] versus 6.5 [3.0] mL.kg-1.min-1, P = .006), whereas there was no difference in insulin or proinsulin concentrations among the groups. In multiple regression analysis, insulin sensitivity was the major determinant of blood pressure. We conclude that in subjects with non-insulin-dependent diabetes mellitus, blood pressure is related to insulin sensitivity but not to fasting levels of insulin, suggesting that hyperinsulinemia is probably not the mediator of this relation.