Diabetes mellitus and hypertension are common diseases that coexist at a greater frequency than chance alone would predict. Hypertension in the diabetic individual markedly increases the risk and accelerates the course of cardiac disease, peripheral vascular disease, stroke, retinopathy, and nephropathy. Our understanding of the factors that markedly increase the frequency of hypertension in the diabetic individual remains incomplete. Diabetic nephropathy is an important factor involved in the development of hypertension in diabetics, particularly type I patients. However, the etiology of hypertension in the majority of diabetic patients cannot be explained by underlying renal disease and remains "essential" in nature. The hallmark of hypertension in type I and type II diabetics appears to be increased peripheral vascular resistance. Increased exchangeable sodium may also play a role in the pathogenesis of blood pressure in diabetics. There is increasing evidence that insulin resistance/hyperinsulinemia may play a key role in the pathogenesis of hypertension in both subtle and overt abnormalities of carbohydrate metabolism. Population studies suggest that elevated insulin levels, which often occurs in type II diabetes mellitus, is an independent risk factor for cardiovascular disease. Other cardiovascular risk factors in diabetic individuals include abnormalities of lipid metabolism, platelet function, and clotting factors. The goal of antihypertensive therapy in the patient with coexistent diabetes is to reduce the inordinate cardiovascular risk as well as lowering blood pressure.

Diabetes mellitus and hypertension.

We followed 1, 134 patients with Type 1 (insulin-dependent) diabetes, diagnosed between 1933 and 1952, until 1982 or death or until their emigration. Their age at onset of diabetes was under 31 years. Information concerning the development of persistent proteinuria was sought in every case. In 104 cases, the data were either questionable or the patient could not be traced. Twenty-nine patients developed non-diabetic proteinuria. Among the remaining 1,001 patients, 406 developed persistent proteinuria (350 died) and 595 did not (166 died). The incidence of persistent proteinuria was highest among men; it decreased with increasing year of diabetes onset from 1933 to 1952, and decreased with increasing age at onset. The relative mortality was extremely high among patients with persistent proteinuria, increasing to a maximum of about 100 at age 35 years. Patients not developing proteinuria had a relatively constant low relative mortality of about 2. The decreasing incidence of persistent proteinuria and the decreasing mortality with increasing calender year of diabetes onset resulted in a 50% increase in life-expectancy among patients diagnosed in 1950 compared with patients diagnosed in 1935. In patients who developed persistent proteinuria, relative mortality was higher in women than men at all ages. In patients who did not develop proteinuria, relative mortality was similar in men and women after the age of 35. Uraemia was the main cause of death in patients with persistent proteinuria, although cardiovascular deaths were more frequent than in patients without proteinuria. Thus, proteinuria is associated not only with death from uraemia but also from cardiovascular disease. It is concluded that the development of persistent proteinuria is a major life-threatening complication in patients with early-onset Type 1 diabetes. Patients who do not develop proteinuria have almost a normal life expectancy.

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The effect of proteinuria on relative mortality in Type 1 (insulin-dependent) diabetes mellitus

https://www.amjmed.com/article/0002-9343(86)90719-9/pdf

Pathogenesis of diabetic microangiopathy. The hemodynamic view

Angiotensin II and other components of the renin-angiotensin-aldosterone system (RAAS) have a central role in the pathogenesis and progression of diabetic renal disease. A study in patients with type 1 diabetes and overt nephropathy found that RAAS inhibition with angiotensin-converting-enzyme (ACE) inhibitors was associated with a reduced risk of progression to end-stage renal disease and mortality compared with non-RAAS-inhibiting drugs. Blood-pressure control was similar between groups and proteinuria reduction was responsible for a large part of the renoprotective and cardioprotective effect. ACE inhibitors can also prevent microalbuminuria in patients with type 2 diabetes who are hypertensive and normoalbuminuric; in addition, ACE inhibitors are cardioprotective even in the early stages of diabetic renal disease. Angiotensin-II-receptor blockers (ARBs) are renoprotective (but not cardioprotective) in patients with type 2 diabetes and overt nephropathy or microalbuminuria. Studies have evaluated the renoprotective effect of other RAAS inhibitors, such as aldosterone antagonists and renin inhibitors, administered either alone or in combination with ACE inhibitors or ARBs. An important task for the future will be identifying which combination of agents achieves the best renoprotection (and cardioprotection) at the lowest cost. Such findings will have major implications, particularly in settings where money and facilities are limited and in settings where renal replacement therapy is not available and the prevention of kidney failure is life saving.

The RAAS in the pathogenesis and treatment of diabetic nephropathy

The transcapillary escape rate, intravascular mass and outflux of albumin were measured in 75 Type 1 (insulin-dependent) diabetic patients. The groups were defined as: group 1: normal urinary albumin excretion, <30 mg/24 h (n=21); group 2: microalbuminuria, 30–300 mg/24 h (n=36); group 3: diabeticnephropathy, <300 mg/24 h (n=18). Fifteen sex- and age-matched non-diabetic persons served as control subjects. The diabetes duration was: group 1: 20±9 years, group 2: 17±5 years, group 3: 19±7 years. The transcapillary escape rate of albumin was similar in controls and group 1 (5.0±1.8 versus 5.2±1.5%) and was significantly higher in the microalbuminuric group 2 and group 3 (8.1±2.2 versus 8.1±2.3 %). The differences were not explained by differences in metabolic control or blood pressure at the time of investigation. The outflux of albumin was also higher in group 2 than in group 1 and controls (7.1 ± 2.0 versus 5.3±1.5 and 5.1±2.0 g/h × 1.73 m2). It was indistinguishable from controls in group 3 (5.8±1.5 g/h × 1.73 m2) because of a reduced intravascular mass of albumin (p<0.01) in group 3. In conclusion, a universal vascular leakage of albumin is an early event in the development of diabetic nephropathy, with the leakage of albumin being fully developed in the microalbuminuric patient. In contrast, long-term diabetic patients with normal urinary albumin excretion have a normal transcapillary escape rate of albumin.

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Increased transcapillary escape rate of albumin in Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Available evidence indicates that poor metabolic control and raised blood pressure each accelerate the development of diabetic microangiopathy. Microangiopathy is associated with excess albumin deposition in capillary basement membranes and it has been suggested that increased extravasation of plasma constituents may lead to basement membrane thickening. We measured the transcapillary escape rate of albumin, an indicator of the rate of extravasation of intravascular albumin from the circulation per unit time, following intravenous injection of 125I-human serum albumin. We examined the independent effects on the transcapillary escape rate of albumin of non-ketotic poor metabolic control, hypertension and microangiopathy. We studied non-diabetic control subjects and diabetic patients, initially when in non-ketotic poor metabolic control and again when control had been improved. We also studied normotensive well-controlled diabetic patients without microangiopathy, normotensive well-controlled diabetic patients with microangiopathy, hypertensive well-controlled diabetic patients without microangiopathy and hypertensive well-controlled diabetic patients with microangiopathy. The transcapillary escape rate of albumin was similar in non-diabetic control subjects (5.5 +/- 0.7%/h) and in both Type 1 (5.3 +/- 1.2%/h) and Type 2 (5.1 +/- 0.6%/h) normotensive diabetic patients without long-term complications. During poor metabolic control the transcapillary escape rate of albumin was significantly higher than in non-diabetic subjects (8.8 +/- 0.8%/h and 5.5 +/- 0.7%/h respectively, p less than 0.01). With improved control values fell significantly to 6.3 +/- 0.9%/h (p less than 0.02), not significantly different from control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

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Poor metabolic control, hypertension and microangiopathy independently increase the transcapillary escape rate of albumin in diabetes.

1. We studied 12 normotensive non-ketotic diabetic patients during poor metabolic control, with sustained hyperglycaemia, and again, after an interval of 3 weeks, when metabolic control was improved. On each occasion we measured blood pressure, total exchangeable sodium, plasma volume, transcapillary escape rate of albumin, and plasma concentrations of angiotensin II and aldosterone. 2. With improved diabetic control there was a small but significant fall in arterial pressure. Total exchangeable sodium was normal when control was poor but rose significantly to above normal with improved control. 3. Plasma volume also rose significantly with improved control, and the transcapillary escape rate of albumin fell and the intravascular mass of albumin rose. 4. Plasma angiotensin II and aldosterone concentrations were significantly above normal during poor metabolic control, but fell to normal with improved control. 5. These findings indicate a resetting of the relationship between blood pressure and exchangeable sodium when diabetic control improves. The association between exchangeable sodium and concentrations of angiotensin II and aldosterone also appears altered in diabetic patients. These changes associated with varying metabolic control must be considered when studying cardiovascular disease in diabetic patients.

Changes in Blood Pressure, Body Fluids, Circulating Angiotensin II and Aldosterone, with Improved Diabetic Control

The concentrations of angiotensin II and aldosterone in plasma were measured in 101 consecutive unselected out-patient diabetic patients and in fifty-three normal controls. The concentration of angiotensin II was similar in diabetics without complications and controls, but was significantly lower in patients with hypertension or peripheral neuropathy. In contrast, plasma aldosterone was not reduced in any sub-group. The concentrations of angiotensin II and aldosterone were positively correlated in controls, in diabetes without complications and in hypertensive diabetics, but this relationship was not found in patients with peripheral neuropathy, retinopathy or nephropathy. There was no evidence of overt hypoaldosteronism in any of the diabetic patients. No individual aldosterone concentration was below the range found in controls and no plasma angiotensin II concentration is reduced in patients with specific diabetic complications such as neuropathy, plasma aldosterone may be maintained by factors other than the renin-angiotensin system. This would explain why hypoaldosteronism is rare among unselected diabetics.

Plasma angiotensin ii and aldosterone in unselected diabetic patients

The prevalence of hypertension was investigated in a systematically chosen sample of patients attending a diabetic clinic. One hundred ninety-one patients were classified as Type 1 (insulin-dependent), 183 were classified as Type 2 (non-insulin-dependent) and 12 were deemed unclassifiable. Two hundred fifty-five control subjects attending non-medical out-patient clinics were also examined under similar conditions. Hypertension was significantly (p<0.001) more common among Type 2 patients (38%) than among Type 1 patients (15%) or control subjects (16%). The difference between Type 2 patients and control subjects, but not between Type 2 and Type 1 patients, persisted when the influences of age and body mass index were controlled. We also investigated the prevalence of hypertension among the siblings of the hypertensive patients identified, together with a matched normotensive group. One hundred eighty-eight siblings were examined and historical details were obtained for a further 451 siblings. When age and body mass index were controlled for in examined siblings, the risk of hypertension was greater in those with a hypertensive proband than in those with a normotensive proband, in the control (p<0.06) and Type 1 (p<0.02) groups. Among the siblings of Type 2 probands, however, the risk of hypertension in those with a normotensive proband Was at least as great as in those with a hypertensive proband, and greater than in those with a normotensive proband in the control (p<0.10) or Type 1 (p<0.05) groups. The prevalence of cardiovascular deaths was also similar in the siblings of normotensive and hypertensive Type 2 probands. We conclude that in our diabetic clinic there is an excess of hypertension among Type 2 patients. There may also be an excess of hypertension among the siblings of Type 2 patients.

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Hypertension in diabetic clinic patients and their siblings

This paper treats the OECD report on Irish education Investment in Education published in 1965 as a ‘cultural stranger’ and assesses its contribution to Irish educational policy up to the present Widely regarded as a major modernizing force in Irish society, this report is perceived to have confronted, penetrated, and changed the insular paradigms governing Irish educational policy, in particular replacing the personal development with the human capital paradigm as the institutional rationale for education The influence of Investment in Education is situated within the economic reconstruction that commenced in the late 1950s, and the lack of contestation and the role of interest groups within the state apparatus and beyond are analysed The expansion of the human capital paradigm to incorporate commercial, vocational, and market interpretations of schooling and the impact of these on the structuration of consciousness within the educational policy‐making community are described The conclusion locates t

D. J. O’Sullivan

Papers

Poor metabolic control, hypertension and microangiopathy independently increase the transcapillary escape rate of albumin in diabetes.

Changes in Blood Pressure, Body Fluids, Circulating Angiotensin II and Aldosterone, with Improved Diabetic Control

Plasma angiotensin ii and aldosterone in unselected diabetic patients

Hypertension in diabetic clinic patients and their siblings

Cultural strangers and educational change: The OECD Report Investment in Education and Irish Educational Policy