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.