Acta Paediatr Suppl 427: 35-8. 1999

Prevention of microvascular complications in diabetic children and adolescents A Verrotti, M Catino, L Di Ricco, A Casani and F Chiarelli Department of Pediatrics, University of Chieti, Chieti, Italy

Verrotti A, Catino M, Di Ricco L, Casani A, Chiarelli F. Prevention of microvascular complications in diabetic children and adolescents. Acta Pzdiatr 1999; Suppl427: 35-8. Stockholm. ISSN 0803-5326 Diabetes mellitus causes profound alterations in many body tissues. Microvascular diabetic complications include diabetic neuropathy, nephropathy and retinopathy. Nephropathy first becomes manifest with hyperfiltration and microalbuminuria. These functional changes evolve over several years to a stage of marked deterioration of renal function. The possible preventive measures are metabolic control, reduction of dietary protein intake and use of ACE-inhibitors. Metabolic control is also important for the prevention of diabetic retinopathy. In fact, patients with HbAlc higher than 10% have an increased risk of progression of retinopathy. Moreover, an accelerated progression of retinopathy has been observed in patients with systemic hypertension following the onset of microalbuminuria. It has been demonstrated that diabetic neuropathy can also be present during childhood; therefore, it is possible to detect electrophysiological abnormalities in children and adolescents with IDDM. Glycaemic and blood pressure control are, so far, the main means for possible prevention or modification of the natural history of diabetic microvascular complications. Tight glycaemic control may have beneficial effects for diabetic neuropathy. In addition, other preventive measures, such as aldose reductase inhibitors, ganglio- sides, neurotrophic vitamins, etc., have been studied in the last years. However, no conclusive results have been obtained so far. 0 Diabetes, microvascular complications, nephropathy, retino-

F Chiarelli, Department of Pediatrics, University of Chieti, Ospedale Policlinico, Via Vestini 5, 66100 Chieti, Italy

pathy

Diabetes mellitus causes profound metabolic alterations in many body tissues, including those involved in general metabolic homoeostasis, such as liver, muscle and adipose tissue, as well as other tissues in which metabolic derangement may contribute to the develop- ment of late complications. Although the hormonal and metabolic environment produced by diabetes is ob- viously common to all tissues, each tissue undergoes specific metabolic alterations in diabetes, according to its morphological, metabolic and functional character- istics.

High glucose concentrations may exert deleterious metabolic effects through various mechanisms, which take place in several tissues. The main mechanisms are: (a) an influence on the activity of enzymes with “low affinity” for glucose, such as aldose reductase; (b) inhibition of key enzymes, such as hepatic pyruvate kinase; (c) stimulation of protein synthesis, including the synthesis of enzyme proteins; (d) glycosylation of macromolecules, such as proteins, lipoproteins, nucleic acids, etc. These mechanisms may be operative in insulin-sensitive tissues, thus contributing to diabetic complications (1).

Complications include both microvascular (diabetic retinopathy, nephropathy, autonomic and peripheral

neuropathy) and macrovascular diseases (lower extre- mity arterial and coronary heart disease). There is great debate concerning the factors that can initiate micro- vascular complications and, consequently, what are the main tools for the prevention of these complications. The aim of this paper is to review the main aspects of appropriate prevention of diabetic microvascular com- plications (retinopathy, nephropathy and neuropathy) (2)-

Nephropath y Diabetic nephropathy first becomes functionally man- ifest with hyperfiltration and microalbuminuria, present in poorly controlled patients or after strenuous exercise. An extended period of elevated glomerular filtration rate follows and may accompany a rising albumin excretion rate (AER). Eventually, the triad of clinical diabetic nephropathy (falling glomerular filtration rate, hypertension and overt proteinuria) will begin to develop and progress inexorably. These functional changes caused by diabetes evolve over several years to a stage of marked diminution in renal function, wherein the renal disease itself may accelerate the

0 Scandinavian University Press 1999. ISSN 0803-5326

36 A Verrotti e f al. ACTA PRDIATR SUPPL 427 (1999)

impairment of the kidney and, without transplantation? the patient will die or face haemodialysis (3). The possible preventive measures can be summarized as follows: improvement of metabolic control; reduction of dietary protein intake and use of ACE-inhibitors.

Several previous reports have suggested a relation- ship between poor blood glucose control and increased urinary albumin excretion (4). More recently in the Diabetes Control and Complications Trial (DCCT), as HbAlc was reduced below 8% there were continuing relative reductions in the risk of complications, whereas there was a slower rate of increase in the risk of hypoglycaemia. Therefore, the DCCT continues to recommend implementation of intensive therapy with the goal of achieving normal glycaemia as early as possible in as many IDDM patients as is safely possible. Nevertheless, a meta-analysis of the effect of intensive therapy on nephropathy (5) showed that, although intensive therapy may delay the progression of micro- vascular complications, the optimal level of glycaemic control to gain maximal protection with minimal side- effects is still to be defined. The target level of glycaemic control and the riskbenefit ratio ought to be individualized for each patient, and, consequently, no universal guidelines can be generalized to all patients. Moreover, the best possible control should be aimed for in all diabetic children and adolescents from the very beginning of the disease, with the aim of reaching HbAlc values of 7.0-7.5%.

The role of dietary protein intake in the prevention of diabetic nephropathy is debated; it has been demon- strated that low protein diets can reduce glomerular pressure and preserve kidney function and structure. Nevertheless, in IDDM patients with normal renal function or incipient renal disease, low protein diets reduce glomerular hyperfiltration. Many studies have demonstrated that in diabetic subjects with microalbu- minuria and glomerular hyperfiltration, short-term diet- ary protein restriction leads to a reduction in albuminuria and glomerular filtration rate (GFR). Consequently, restriction of protein intake can substan- tially slow the progression of diabetic renal disease in patients with diabetic nephropathy. Protein intake below 0.6 g/kg/d may be associated with protein malnutrition and the aim of a diet should be to reduce protein intake to a non-harmful yet achievable level by the majority of patients (i.e. 1.0-1.3 g/kg/d) (2).

In children with microalbuminuria (AER 20-200 (pg/min) blood glucose control should be improved during a period of 6 months and microalbuminuria should be monitored closely. If microalbuminuria disappears or improves there is no indication for pharmacological intervention. However, if the status of microalbuminuria deteriorates even if the blood glucose control improves and blood pressure is within the normal limits, antihypertensive treatment with an ACE-inhibitor should be instituted (4), providing that dietary protein intake is moderate (1.0-1.3 g/kg/d).

Of all antihypertensive agents, inhibitors of angio- tensin-converting enzyme (ACE) are regarded as particularly effective in limiting renal disease progres- sion, because of possible beneficial influences on kidney function, which are independent from the effects on systemic blood pressure. These drugs significantly limit the progression of renal disease in patients with macroalbuminuria and there were indications that this beneficial effect also occurs in patients with micro- albuminuria. Lisinopril is of clinical benefit to people with IDDM who have early sign of renal disease without hypertension. The greatest clinical effect is observed in those with microalbuminuria (AER > 20 pg/min), but the exact threshold at which to start treatment requires long-term follow-up to assess the impact of a modest protective effect in those with normoalbuminuria, particularly those with AER greater than 5 pg/min. It is clear, however, that guidelines for the care of people with JDDM should now include the treatment of early-stage renal disease with ACE- inhibitors, even in normotensive patients (6).

Retinopathy Several factors besides duration of disease have been shown to be associated with severe retinopathy, such as metabolic control and blood pressure (7). With regard to metabolic control, two statistical models appropriately explained the relationship between glycaemic control and the risk of early background retinopathy; (1) a continuos exponential relationship as described by DCCT and; (2) the presence of a threshold HbAlc level at 9% (corresponding to a HbAlc of 8.4% in the DCCT study). Moreover, the development of angio- pathy may be accelerated during puberty. When children with prepubertal and pubertal diabetes duration were compared in the Berlin Retinopathy Study with respect to the onset of incipient and background retinopathy, it was observed that children with pre- pubertal onset developed retinopathy 3 y before chil- dren with postpubertal diabetes onset, indicating the importance of prepubertal period on the development of diabetic eye disease. However, this difference had increased to more than 7 y for the onset of background retinopathy, indicating an accelerated pace of the development of microangiopathy during sexual matura- tion (8). It is well known that the DCCT has confirmed the role of metabolic control for the prevention of diabetic retinopathy. In particular, in the DCCT (as well as many other studies), those patients who maintained improved glycosylated haemoglobin levels showed slower progression of retinopathy, with a cut-off of glycosylated haemoglobin (HbAlc) of 8.7%. Those with HbAlc higher than 10% had an increased risk of progression. The DCCT suggested that long periods of improved glycaemic control are necessary to demon- strate any beneficial effect. The DCCT study also

ACTA PEDIATR SUPPL 427 (1999) Prevention of complications in children with diabetes 37

demonstrated that intensive therapy with the goal of lowering plasma glucose concentration delays the onset and slows the progression of early diabetic retinopathy in adolescents with IDDM. In the primary prevention cohort, intensive therapy decreased the risk of having retinopathy by 53% in comparison with conventional therapy. In the secondary intervention cohort, intensive therapy decreased the risk of retinopathy progression by 70%.

Accelerated progression of diabetic retinopathy has been observed in patients with systemic hypertension (9). Until therapies are in place to prevent or cure diabetic retinopathy and other complications, the emphasis must be placed on identification, careful follow-up, and timely laser photocoagulation of patients with diabetic retinopathy and diabetic eye disease. Patients should be informed of the relationship between quality of diabetes control and the risk of development of ocular and other complications, as the rationale for their partnership with the healthcare team (10).

Neuropath y In the last years, it has been demonstrated that diabetic neuropathy can be present also during childhood and consequently electrophysiological abnormalities can be detected in some children and adolescents with type 1 diabetes mellitus. The existence of such a “metabolic” component to nerve conduction slowing in diabetes is suggested by several studies in which nerve conduction velocity correlates with glycosylated haemoglobin or other measures of diabetic control, or improved glycaemic control is associated with an improvement in peripheral nerve function (11). In particular, the DCCT group demonstrated that motor and sensory nerve conduction velocities were faster in intensively treated subjects compared with the conventionally treated group; nevertheless, in the adolescent cohort, while neuropathy was not sufficiently common to draw conclusions, nerve conduction was significantly slower in the conventionally treated group. This difference seemed to be due to improvement in the intensive group as well as deterioration in the conventional group, whose mean HbAlc was 9.76%. Even though electrical studies have indicated that abnormal nerve conduction is not reversible by improved diabetic control, many patients report improvement in symptoms with better control (9). The important role played by elevated blood

vitamins, dietary myoinositol intake, isaxonine. Among these agents aldose reductase inhibitors seems to have an important role: in fact, the increase polyol pathway activity related to the higher blood glucose levels has been shown to induce an accumulation of sorbitol and fructose in tissues of diabetics, with aldose reductase and sorbitol dehydrogenase enzymatic activities. It has been postulated that inhibition of the aldose reductase activity blocking the accumulation of sorbitol in nerves could induce an improvement of neuropathy in diabetic subjects.

The aldose reductase inhibitor sorbitol has been studied extensively in vivo over the past few years. Some authors have reported a few positive results on some symptoms of diabetic neuropathy, whereas the lack of a significant improvement was underlined by other studies (12).

In conclusion, a cure of IDDM, with total prevention of complications, is the goal of most of our patients. The DCCT has demonstrated the importance and feasibility of long-term improved glycaemic control in adolescents as well as in adults with IDDM. Although prepubertal children appear to be somewhat protected and severe hypoglycaemia is likely to be more detrimental, one cannot apply the DCCT findings to this age group. At all ages, however, therapy should be aimed at achieving the best glycaemic control possible for each individual. Therefore, it seems that if chronic complications of diabetes are to be prevented, the time of intervention should be in the early years during childhood and adolescence (before structural damage has occurred) (13) and from the very beginning of diabetes. Satisfac- tory long-term glycaemic control is, so far, the best mean for prevention of diabetic complications. Blood pressure control has shown to be effective in slowing the progression of diabetic nephropathy and probably, retinopathy.

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