Alteration of the clotting system in diabetic patients is presently the focus of increasing interest due to its potential role in the pathogenesis of large and smallvessel disease in diabetes mellitus. It is believed that enhanced pro-coagulant activity is linked to the excessive cardiovascular morbidity and mortality among diabetic patients which have not been fully explained by major risk factors such as arterial hypertension, cigarette smoking and hypercholesterolaemia. Perturbance of haemostasis has also been implicated in the development of complications such as nephropathy and retinopathy and in the acceleration of atherogenesis observed in diabetic patients [1,2]. Diabetologia (1996Diabetologia ( ) 39: 1455Diabetologia ( -1461 Protein C activation in NIDDM patients Summary Enhanced activation of the clotting system has been recently implicated in the pathogenesis of vascular complications in patients with diabetes mellitus. Abnormalities of the anticoagulant system may constitute a potential trigger factor for the haemostatic activation observed in diabetic subjects. The current study aimed to evaluate anticoagulant activity in diabetic patients by assessing the plasma levels of activated protein C-protein C inhibitor complex; and by measuring the anticoagulant response to exogenous thrombomodulin. This study comprised 61 patients (34 men, 27 women) with non-insulin-dependent diabetes mellitus (NIDDM) of whom 22 showed microalbuminuria and 39 normoalbuminuria. Data obtained in 31 non-obese and non-diabetic subjects were available for comparison. The plasma levels of fibrinogen (p < 0.02), prothrombin fragment 1 + 2 (p < 0.05), fibrin monomer (p < 0.0001), protein C antigen (p < 0.005), total protein S antigen (p < 0.02), soluble thrombomodulin (p < 0.005) and soluble Eselectin (p < 0.005) were significantly higher in diabetic patients than in healthy subjects. The plasma level of activated protein C-protein C inhibitor complex (7.4 ± 3.8 vs 3.0 ± 0.4 pmol/l) was significantly higher (p < 0.0001) and the anticoagulant response to exogenous thrombomodulin (23.4 ± 2.6 vs 35.3 ± 3.0 ng/ml) was markedly lower (p = 0.005) in all diabetic patients than in healthy subjects. Cases with microalbuminuria presented low plasma levels of activated protein C-protein C inhibitor complex (5.5 ± 0.6 vs 8.6 ± 0.7 pmol/l, p < 0.05) and significantly decreased values of the anticoagulant response to exogenous thrombomodulin (16.5 ± 2.9 vs 23.4 ± 2.6 %, p = 0.03) as compared to those with normoalbuminuria. The present study suggests that the hyper-coagulable state in NIDDM is associated with an increased activation of protein C but with a poor plasma reactivity to the anticoagulant effect of thrombomodulin.

The allele encoding threonine in the FABP2 does not predispose to Type 2 DM or insulin resistance in the Japanese population.

This study was undertaken to investigate the relationship of the serum sex hormone-binding globulin (SHBG) levels with the plasma insulin concentration and with the insulin resistance in male subjects with noninsulin-dependent diabetes mellitus (NIDDM). This investigation comprised 12 patients with NIDDM and 16 normal subjects matched for age, sex, and body mass index (BMI). There was a significant increase in insulin levels (P < 0.03) and a decrease in SHBG levels (P < 0.01) in the diabetic group as compared with those of the normal group. The sex hormone and plasma insulin levels were measured in NIDDM patients undergoing exercise and dietary therapy. Insulin sensitivity was evaluated by the hyperinsulinemic euglycemic clamp technique expressed as the glucose infusion rate (GIR) before and after the treatment. The SHBG levels correlated significantly with the insulin concentrations (r = -0.643, P < 0.05) and with the GIR (r = 0.615, P < 0.05) before the treatment. The SHBG levels (P < 0.02) and GIR (P < 0.01) increased, and the insulin concentrations (P < 0.01) decreased significantly during the treatment. The SHBG levels showed a negative and significant correlation with the plasma insulin concentrations at the end of the clamp study before (r = -0.615, P < 0.05) and after (r = -0.626, P < 0.05) the treatment. These findings suggest that, in the hyperinsulinemic state, plasma insulin has a direct effect on the SHBG levels. SHBG levels decreased significantly during the clamp study before (P < 0.02) and after (P < 0.01) the treatment. This may represent the acute effect of insulin on the SHBG levels. Briefly, these results suggest that insulin may directly affect the SHBG levels and that SHBG may constitute an index of the insulin resistance only in the hyperinsulinemic state.

The chemical specificity and structural requirements of short-chain fatty acids (SCFAs) in stimulating pancreatic endocrine responses was investigated in conscious sheep. Normal SCFAs with one to eight carbons were injected intravenously at seven doses of 39-2,500 mumol/kg body wt. The isomers or derivatives of SCFAs were administered at 625 mumol/kg body wt. Analysis of dose-response curves showed that n-butyric acid (4 carbons in the molecule) was most effective for both insulin and glucagon secretion among the normal SCFAs tested. In addition, one carboxylic group was absolutely required, since hormone secretion was significantly reduced or abolished with compounds in which the carboxylic element was replaced by other groups and with dicarboxylic acids. The form of the hydrocarbon chain (branched, cyclic, or benzoic ring) also affected hormone secretory activity. Most of the compounds that replaced hydrogen in the hydrocarbon chain by other groups at various positions reduced or abolished the hormone secretory effect obtained by n-butyric acid. In conclusion, a monocarboxylic acid with several numbers of hydrocarbons was required for insulin or glucagon secretion. These results suggest that the pancreatic endocrine system can recognize the chemical structure of SCFAs in detail and induce hormone secretion in sheep.

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