Background Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus (IDDM). We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications. Methods A total of 1441 patients with IDDM--726 with no retinopathy at base line (the primary-prevention cohort) and 715 with mild retinopathy (the secondary-intervention cohort) were randomly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections. The patients were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. Results In the primary-prevention cohort, intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent (95 percent confidence interval, 62 to 85 percent), as compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54 percent (95 percent confidence interval, 39 to 66 percent) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent (95 percent confidence interval, 14 to 67 percent). In the two cohorts combined, intensive therapy reduced the occurrence of microalbuminuria (urinary albumin excretion of > or = 40 mg per 24 hours) by 39 percent (95 percent confidence interval, 21 to 52 percent), that of albuminuria (urinary albumin excretion of > or = 300 mg per 24 hours) by 54 percent (95 percent confidence interval 19 to 74 percent), and that of clinical neuropathy by 60 percent (95 percent confidence interval, 38 to 74 percent). The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia. Conclusions Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy, nephropathy, and neuropathy in patients with IDDM.

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.

Objective: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes. Design: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <.180/105 mm Hg. Setting 20 hospital based clinics in England, Scotland, and Northern Ireland. Subjects: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years. Main outcome measures: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography. Results: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P< 0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P= 0.0046), 32% in deaths related to diabetes (6% to 51%) (P= 0.019), 44% in strokes (11% to 65%) (P= 0.013), and 37% in microvascular end points (11% to 56%) (P= 0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P= 0.0004) and a 47% reduced risk (7% to 70%) (P = 0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures. Conclusion: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.

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Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38

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.

It is increasingly apparent that not only is a cure for the current worldwide diabetes epidemic required, but also for its major complications, affecting both small and large blood vessels. These complications occur in the majority of individuals with both type 1 and type 2 diabetes. Among the most prevalent microvascular complications are kidney disease, blindness, and amputations, with current therapies only slowing disease progression. Impaired kidney function, exhibited as a reduced glomerular filtration rate, is also a major risk factor for macrovascular complications, such as heart attacks and strokes. There have been a large number of new therapies tested in clinical trials for diabetic complications, with, in general, rather disappointing results. Indeed, it remains to be fully defined as to which pathways in diabetic complications are essentially protective rather than pathological, in terms of their effects on the underlying disease process. Furthermore, seemingly independent pathways are also showing significant interactions with each other to exacerbate pathology. Interestingly, some of these pathways may not only play key roles in complications but also in the development of diabetes per se. This review aims to comprehensively discuss the well validated, as well as putative mechanisms involved in the development of diabetic complications. In addition, new fields of research, which warrant further investigation as potential therapeutic targets of the future, will be highlighted.

Mechanisms of Diabetic Complications

In a population-based study in southern Wisconsin, 996 insulin-taking, younger-onset diabetic persons were examined using standard protocols to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The prevalence of diabetic retinopathy varied from 17% to 97.5% in persons with diabetes for less than five years and 15 or more years, respectively. Proliferative retinopathy varied from 1.2% to 67% in persons with diabetes for less than ten years and 35 or more years, respectively. For persons with diabetes of 10 years' duration or less, the Cox regression model relates the severity or retinopathy to longer duration, older age at examination, and higher levels of glycosylated hemoglobin. After ten years of diabetes, severity of retinopathy was related to longer duration, high levels of glycosylated hemoglobin, presence of proteinuria, higher diastolic BP, and male sex.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy: II. Prevalence and Risk of Diabetic Retinopathy When Age at Diagnosis Is Less Than 30 Years

Diabetes is now regarded as an epidemic, with the population of patients expected to rise to 380 million by 2025. Tragically, this will lead to approximately 4 million people around the world losing their sight from diabetic retinopathy, the leading cause of blindness in patients aged 20 to 74 years. The risk of development and progression of diabetic retinopathy is closely associated with the type and duration of diabetes, blood glucose, blood pressure, and possibly lipids. Although landmark cross-sectional studies have confirmed the strong relationship between chronic hyperglycaemia and the development and progression of diabetic retinopathy, the underlying mechanism of how hyperglycaemia causes retinal microvascular damage remains unclear. Continued research worldwide has focussed on understanding the pathogenic mechanisms with the ultimate goal to prevent DR. The aim of this paper is to introduce the multiple interconnecting biochemical pathways that have been proposed and tested as key contributors in the development of DR, namely, increased polyol pathway, activation of protein kinase C (PKC), increased expression of growth factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), haemodynamic changes, accelerated formation of advanced glycation endproducts (AGEs), oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and subclinical inflammation and capillary occlusion. New pharmacological therapies based on some of these underlying pathogenic mechanisms are also discussed.

https://downloads.hindawi.com/archive/2013/343560.pdf

Pathophysiology of Diabetic Retinopathy

Objective To determine the relationship between tight blood pressure (BP) control and the different aspects of diabetic retinopathy in patients with type 2 diabetes mellitus (DM). Setting Nineteen hospital-based clinics in England, Scotland, and Northern Ireland. Design Outcome of retinopathy status assessed by 4-field retinal photography related to allocation within a randomized controlled trial comparing a tight BP control policy aiming for a BP less than 150/85 mm Hg with a less tight BP control policy aiming for a BP less than 180/105 mm Hg. Subjects One thousand one hundred forty-eight hypertensive patients with type 2 DM were studied. These patients had type 2 DM for a mean duration of 2.6 years at the inception of the Hypertension in Diabetes Study, had a mean age of 56 years; and had a mean BP of 160/94 mm Hg. Seven hundred fifty-eight patients were allocated to a tight BP control policy with angiotensin-converting enzyme inhibitor or beta-blockers as the main therapy; 390 were allocated to a less tight BP control policy. Main outcome measures Deterioration of retinopathy (>/=2-step change on a modified Early Treatment Diabetic Retinopathy Study [ETDRS] final scale), together with end points (photocoagulation, vitreous hemorrhage, and cataract extraction) and analysis of specific lesions (microaneurysms, hard exudates, and cotton-wool spots). Visual acuity was assessed at 3-year intervals using ETDRS logarithm of the minimum angle of resolution charts. Blindness was monitored as an end point with the criterion of Snellen chart assessment at 6/60 or worse. Results By 4.5 years after randomization, there was a highly significant difference in microaneurysm count with 23.3% in the tight BP control group and 33.5% in the less tight BP control group having 5 or more microaneurysms (relative risk [RR], 0.70; P = .003). The effect continued to 7.5 years (RR, 0.66; P /=6/60) in 1 eye was 18/758 for the tight BP control group compared with 12/390 for less tight BP control group. These equate to absolute risks of 3.1 to 4.1 per 1000 patient-years, respectively (P = .046; RR, 0.76; 99% confidence interval, 0.29-1.99). There was no detectable difference in outcome between the 2 randomized therapies of angiotensin-converting enzyme inhibition and beta-blockade. Conclusions High BP is detrimental to each aspect of diabetic retinopathy; a tight BP control policy reduces the risk of clinical complications from diabetic eye disease.

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Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69.

OBJECTIVES--(a) To report on the basic parameters of retinal blood flow in a population of diabetic patients with and without retinopathy and non-diabetic controls; (b) to formulate a haemodynamic model for the pathogenesis of diabetic retinopathy from this and other studies. DESIGN--Laser-Doppler velocimetry and computerised image analysis to determine retinal blood flow in a large cross sectional study. SETTING--Diabetic retinopathy outpatient clinic. SUBJECTS--24 non-diabetic controls and 76 diabetic subjects were studied (63 patients with insulin dependent diabetes, 13 with non-insulin dependent diabetes). Of the diabetic subjects, 12 had no diabetic retinopathy, 27 had background retinopathy, 13 had pre-proliferative retinopathy, 12 had proliferative retinopathy, and 12 had had pan-retinal photocoagulation for proliferative retinopathy. MAIN OUTCOME MEASURES--Retinal blood flow (microliters/min) and conductance (rate of flow per unit of perfusion pressure). RESULTS--In comparison with non-diabetic controls (9.52 microliters/min) and diabetic patients with no diabetic retinopathy (9.12 microliters/min) retinal blood flow was significantly increased in all grades of untreated diabetic retinopathy (background 12.13 microliters/min, pre-proliferative 15.27 microliters/min, proliferative 13.88 microliters/min). There was a significant decrease in flow after pan-retinal photocoagulation in comparison with all the other groups studied (4.48 microliters/min). Conductance of the retinal circulation was higher in the untreated diabetic retinopathy groups. These results were independent of age, sex, type of diabetes, duration of diabetes, glycated haemoglobin concentration, blood glucose concentration, blood pressure, and intraocular pressure. CONCLUSIONS--Retinal blood flow is significantly increased in diabetic retinopathy in comparison with non-diabetic controls and diabetic subjects with no retinopathy. This has implications for controlling hypertension and hyperglycaemia as a strategy in reducing morbidity from diabetic retinopathy.

https://www.bmj.com/content/bmj/305/6855/678.full.pdf

Retinal blood flow in diabetic retinopathy.

Several mechanisms are implicated in the pathogenesis of diabetic retinopathy. They include biochemical, hemodynamic, and hormonal factors, all of which have an important role in the development of diabetic retinopathy. These factors are not independent of each other, but rather they interact and together are responsible for the well-known lesions of vascular occlusion, microaneurysms, hemorrhages' hard exudates, and eventually new vessel formation.

Role of Blood Flow and Impaired Autoregulation in the Pathogenesis of Diabetic Retinopathy

Retinal blood flow was studied in 9 normal volunteers and 36 diabetic patients. The method used was based on the measurement of the mean transit time of flourescein in the superior temporal quandrant of the retina and on estimation of the vascular volume by measuring vessels diameters. The results showed that patients with mild or no retinopathy had significantly increased volume flow compared with normals, those with moderate retinopathy had a slight but not significant increase and those with severe retinopathy had blood flow similar to that found in normals. The mean transit time was reduced significantly in those with mild or no retinopathy, but was similar to normals in those with moderate and severe retinopathy. Following succesful pituitary ablation and photocoagulation retinal blood flow was reduced compared with pre-treatment studies.

/pdf/the-retinal-blood-flow-in-diabetes-4rkm43mjet.pdf

Eva M. Kohner

Papers

Pathophysiology of Diabetic Retinopathy

Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69.

Retinal blood flow in diabetic retinopathy.

Role of Blood Flow and Impaired Autoregulation in the Pathogenesis of Diabetic Retinopathy

The retinal blood flow in diabetes.