Takao Miyata

Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study

To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl.

Effect on insulin sensitivity of angiotensin converting enzyme inhibitors with or without a sulphydryl group: bradykinin may improve insulin resistance in dogs and humans.

SummaryThe present study compared the effect on insulin sensitivity of ACE inhibitors with a sulphydryl group (captopril) or those without a sulphydryl group (delapril and enalapril) during the hyperinsulinaemic euglycaemic clamp test in both animal and clinical experiments. A possible contribution of bradykinin to the improvement of insulin sensitivity by ACE-inhibition was also studied. In healthy control and depancreatized dog experiments, administration of captopril either intravenously (3.0 mmol · kg−1) or orally (5.0 mmol · kg−1) increased insulin sensitivity indices and plasma bradykinin concentrations. In comparison, intravenous administration of an active metabolite of delapril (3.0 mmol · kg−1) and oral administration of either delapril or enalapril (5.0 mmol · kg−1) showed slight, but not significant increases in insulin sensitivity indices and plasma bradykinin concentrations. Infusion of a bradykinin antagonist (N-α-adamantaneacetyl-d-Arg-[Hyp3, Thi5,8,d-Phe7]-bradykinin) (0.5 nmol · kg−1 · min−1) abolished the effect of captopril on insulin sensitivity. Furthermore, intravenous administration of bradykinin (0.1 nmol · kg−1 · min−1) increased insulin sensitivity indices. In clinical experiments, insulin sensitivity indices decreased in the following order: normotensive healthy subjects, hypertensive non-diabetic patients, normotensive NIDDM patients and hypertensive NIDDM patients. In these four groups, oral administration of captopril (2.0 mmol · kg−1) significantly increased insulin sensitivity indices, and a concomitant increase in plasma bradykinin concentrations was observed. By contrast, oral administration of enalapril or delapril showed slight, but not significant effects on insulin sensitivity indices and plasma bradykinin concentrations. From these studies, it is concluded that ACE inhibitors with a sulphydryl group have more potent action on the improvement in insulin sensitivity than those without a sulphydryl group. Bradykinin may also possibly be involved in the mechanism underlying the improvement in insulin sensitivity associated with ACE-inhibition.

Effect of α2-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in Type 2 (non-insulin-dependent) diabetes mellitus

SummaryThe role of epinephrine in platelet activation and the effect of an α2-adrenoceptor antagonist, midaglizole, during insulin-induced hypoglycaemia in Type 2 (noninsulin-dependent) diabetes mellitus were examined. The action of midaglizole as a platelet α2-antagonist was confirmed by in vitro studies using platelet-rich plasma and washed platelet suspension. Hypoglycaemia was induced by a bolus injection of short-acting insulin in 24 diabetic patients. They were divided into two groups, a control group (n=12) and an α2-group (n=12), and midaglizole was administered orally 60 min before insulin injection in the latter. Blood glucose and plasma C-peptide levels were significantly decreased (p<0.005) by insulin injection in both groups. Counter-regulatory hormones, including epinephrine, and arginine vasopressin were similarly increased at the hypoglycaemic nadir compared with the levels at 0 min in both groups. Plasma β-thromboglobulin was increased at the hypoglycaemic nadir (165.5±12.6ng/ml) compared with the level at 0 min (121.0±11.5, p<0.005) in the control group, whereas no significant increase was demonstrated in the α2 group. These results suggest that plasma epinephrine plays an important role in platelet activation during hypoglycaemia in Type 2 diabetes mellitus, and that the platelet activation is prevented by α2-adrenoceptor antagonist.