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Hypertension in the course of insulin dependent diabetes mellitus and its pathogenetic mechanisms
Hypertensionin the Courseof Insulin DependentDiabetes Mellitus and Its PathogeneticMechanisms
Bo Feldt-Rasmussen, Kirsten Tonny Torsten
MD,
Nergaard, Jensen, Decker&
DMSc
MD MD MD,
DMSc
Steno Memorial Hospital DK-2820 Gent&e Denmark
INTRODUCTION Arterial hypertension is one of the keystones in the syndrome of clinical diabetic nephropathy, and the prevalence of hypertension is high in patients with insulin-dependent diabetes mellitus (IDDM).’ Hypertension is important for the progression of diabetic nephropathy’ and is associated with an increased incidence of other micro- and macrovascular complications, but it is not known whether it also plays a role in the pathogenesis of diabetic nephropathy. In fact, there are indications that hypertension plays only a secondary, although very important, role as recently reviewed by Deckert et aL4 This paper will present our present knowledge of the course of hypertension in IDDM patients developing nephropathy and, based upon this data, will discuss whether or not it has a primary role in the pathogenesis of diabetic nephropathy. In addition, a hypothesis of sodium-volume expansion causing hypertension in diabetic nephropathy will be discussed.
THE TIME COURSE
Reprint requests: Bo Feldt-Rasmussen, MD, DMSc, Steno Memorial Hospital, DK-2820 Gentofte, Denmark.
60
OF HYPERTENSION
Two studies indicate a predisposition to essential hypertension in IDDM patients who develop nephropathy. 5v6 The observations were, however, not confirmed in a Danish study comprising more probands and their parents than the previous studies.’ If there is no predisposition to hypertension, the question remains: When does this gradual rise in blood pressure begin? It is not present at onset of diabetes, because at that time, the blood pressure was normal in patients who later developed clinical nephropathy, and similar to that of patients who survived their disease for more than 40 years.6 The blood pressure is also normal in long-term IDDM patients with a urinary albumin excretion (UalbV) in the normal (~30 mg/24h) or slightly elevated (30-100 mg/24h) range.4 In contrast, a slight but significant elevation of blood pressure is present in IDDM patients with microalbuminuria.B-ll In these patients, we have observed a significant increase in diastolic blood pressure by serial blood pressure measurements over a 2 year prospective study period.12 The estimated annual increase in mean blood pressure was 2.7 mmHg, indicating a progression from normotensive to hypertensive levels within an 8 year period.12 The key question: Which comes first, increasing UalbV or blood pressure rise, seems to have been answered recently by Mathiesen et al.13 They followed 200 normotensive patients with IDDM and normal UalbV for 5 years. Fifteen patients developed persistent microalbuminuria without detectable changes in blood pressure until 1 or 2 years later. Therefore, a mechanism different from arterial hypertension must explain this increased transglomerular albumin escape.4 In further support of the hypothesis that an increase in blood pressure is not the primary event in the pathogenesis of diabetic nephropathy, we recently identified asubpopulation of IDDM patients with essential hypertension. The prevalence was similar to that of the background population. They all remained normoalbuminuric over the 4 years of observation (unpublished results). This demonstration of long-term hypertension without development of microalbuminuria or nephropathy, also supports the hypothesis that hypertension is, in fact, a secondary rather than primary event in the pathogenesis of diabetic nephropathy. This is not to deny the fact that hypertension has a deleterious effect on the progression of established diabetic renal disease (presence of persistent microalbuminuria).
HYPERTENSIONIN IDDM
61
kidney function in diabetic nephropathy. Br Med J 294:1443-
PATHOGENETIC MECHANISMS The pathophysiology of hypertension in diabetes is poorly understood. There is, at present, some evidence in favour of sodium-volume expansion playing a central role.14 Exchangeable sodium is elevated in normotensive IDDM as well as NIDDM patients free of microvascular complications,‘“16 was highest in patients with clinical nephropathy,16 and correlated with the mean blood pressure in a group of patients with microalbuminuria.14 The increase is accompanied by a concomittant increase in extracellular fluid volume (ECV).‘4,‘7,‘6 One group found the ECV increased only in patients with clinical nephropathy. lg Among the possible mechanisms for this sodium-provoked volume expansion are increased insulin-induced or glucose-coupled tubular reabsorption of sodium in the distal tubules, an effect of insulin which has been repeatedly demonstrated.2’t23 This was also demonstrated in a simple clinical set-up when an acute sodium load was retained in insulin treated (peripheral hyperinsulinemia) IDDM patients compared to normal controIs.24 The increased tubular reabsorption of sodium in IDDM patients with normal UalbV is also interesting in relation to the increased glomerular filtration rate (GFR) characteristic of these patients. According to the hypothesis of Leyssac, changes in GFR are secondary to alterations in the proximal tubular reabsorption rate of sodium and water.25 We have, therefore, hypothesized that the hyperfiltration of uncomplicated diabetes is secondary to insulin and/or glucose induced tubular reabsorption of sodium. Recent results are in favour of this hypothesis.22 We, therefore, speculated as to whether the blood pressure starts to increase in IDDM patients if the increased GFR, compensating for the sodium retention caused by peripheral hyperinsulinemia during insulin treatment, starts to decline.26 The pressor hormones will not be discussed in detail here, but there is much confusion in this field. At present, the catecholamines and renin-angiotensin-aldosterone system have not been proven to play any significant role.26
SUMMARY All IDDM patients without late complications have blood pressures similar to the nondiabetic background population, and those who develop clinical nephropathy in Denmark have no familial predisposition to hypertension. Blood pressure remains normal until after development of microalbuminuria, indicating no primary role for hypertension in the pathogenesis of nephropathy. When microalbuminuria is present it does, however, play a crucial role in the progression of nephropathy. Sodium retention, possibly induced by hyperinsulinemia, and perhaps glucose-coupled sodium reabsorption in insulin treated patients, seem to play a central role in elevating the blood pressure, but this needs further clarification.
REFERENCES 1. Major SG: Blood pressure in diabetes mellitus: A statistical study. Arch Intern Med 44:797-812,1929.
2. Parving H-H, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PAA: Effect of antihypertensive treatment on
1447,1987.
3. Drury PL: Diabetes and arterial hypertension. Diabetologia 24:19, 1983.
4. Deckerl T, Feldt-Rasmussen
5. 6.
7. 8. 9. 10. 11.
B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A: Albumin&a reflects widespread vascular damage. The Steno Hypothesis. Diabetologia 32:219-226, 1989. Viberti GC, Keen H, Wiseman M: Raised arterial pressure in parents of proteinuric insulin dependent diabetics. Br Med J 295515-517, 1987. Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti GC: Increased sodium-lithium countertransporl activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 3:146-l 50.1988. Norrgaard K, Jensen JS, Mathiesen ER, et al: Increased blood pressure and red cell sodium-lithium countertransport activity are not inherited in diabetic neohrooathv. Diabetes 38:15A, 1989. Feldt-Rasmussen 8, Borch-Johnsen K, Mathiesen ER: Hypertension in diabetes as related to nephropathy. Early blood pressure changes. Hweflension 7 fsuppl21:18-20. 1985. Mathiesen ER, Oxenball B, Johansen K, Svendsen PAA, Deckeri T: Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 26:40&410.1984. Christensen CK, Mogensen CE: The course of incipient diabetic nephropathy: Studies of albumin excretion and blood pressure. Diabetic Medicine 2:97-l 02. 1985. Wiseman M, Viberti GC, Mackintosh D, Jarrett RJ, Keen H: GlycaTmia, arterial pressure and micrpalbuminuria in type 1 (li;m&n-dependent) diabetes mellltus. D/abeto/ogfa 26:401-405,
12. FeldtlRasmussen B, Mathiesen ER, Decked T: Effect of two years of strict metabolic control on progression of incipient neohrooathv in insulin-deoendent diabetes. Lancet 11:130013b4 1’986: 13. Mathiesen ER, Rlann B, Jensen T, Storm B, Deckerl T: Microalbuminuria precedes elevation in blood pressure in diabetic nephropathy. Diabetolooia 31:519A, 1988. 14. Feldt-Rasmussen B, Mathiesen ER, Deckert T, et al: Central role for sodium in the pathogenesis of blood pressure changes independent of angtotensin, aldosterone and catecholamines in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30:61 O617,1987. 15. DeChatel R, Weidman P, Flammer J, et al: Sodium, renin, aldosterone, catecholamines and blood pressure in diabetes mellitus. Kidney Int 12:412421, 1977. 16. O’Hare JA, Ferris JB, Brady D, Twomey B, O’Sullivan DJ: Exchangeable sodium and renin in hypertensive diabetic patients with and without nephropathy. Hypertension 7 (suppl 2)X&48, 1985. 17. Fauchald P, Norseth J, Jervell J: Transcapillary colloid osmotic gradient, plasmavolume and interstitial fluid volume in long-term type 1 (insulin-dependent) diabetes. Diabetologia 28:269-273, 1985. 18. Briichner-Morlensen J: Glomerular filtration rate and extracellular fluid volumes during normoglycemia and moderate hyperglycemia in diabetics. Stand J C/in Lab /west 32:31 l-31 6. 1973. 19. Hommel E, Mathiesen ER, Giese J, Nielsen MD, Schiitten HJ, Parving H-H: On the pathogenesis of arterial blood pressure elevation early in the course of diabetic nephropathy. Stand J C/in Lab Invest 49:537-544, 1989. 20. Burg MB: Renal handling of sodium, chloride, water, amino acids and glucose. in Brenner BM, Rector FC, (eds), The Kidney, Philadelphia, W.B. Saunders, 328-370, 1981. 21. De Fronzo R: The effect of insulin on renal sodium metabolism. Diabetologia 21 :165-l 71, 1981. 22. NDrgaard K, Jensen T, Sktt P, et al: Volume expansion during hyperinsulinemia induces a parallel increase in glomerular filtration rate and lithium clearance in normal man. Diabetologia 32:523 A, 1989. 23. Skpltt P, Mathiesen ER, Hommel E, Gall MA, Bruun NE, Parving H-H: The increased proximal tubular reabsorption of sodium and
62
water is maintained in long-term insulin-dependent diabetics with early nephropathy. Stand J C/in Lab Invest 49:419-425,1989. 24. Roland JM, O’Hare JP, Walters G, Corral1 RJM: Sodium retention in response to saline infusion in uncomplicated diabetes mellitus. Diabetes Res 3:213-2151988. 25. Leyssac PP: The renin angiotensin system and kidney function. A
FELDT-RASMUSSEN ET AL.
review of contributions to a new theory. Acta Physiol Stand Suppl 442%52,1978. 28. Feldt-Rasmussen B: Microalbuminuria and clinical nephropathy in type 1 (insulin-dependent) diabetes mellitus: Pathophysiological mechanisms and intervention studies. (Thesis) Dan Med Bull 38:405-415,1989.
Bo Feldt-Rasmussen, Kirsten Tonny Torsten
MD,
Nergaard, Jensen, Decker&
DMSc
MD MD MD,
DMSc
Steno Memorial Hospital DK-2820 Gent&e Denmark
INTRODUCTION Arterial hypertension is one of the keystones in the syndrome of clinical diabetic nephropathy, and the prevalence of hypertension is high in patients with insulin-dependent diabetes mellitus (IDDM).’ Hypertension is important for the progression of diabetic nephropathy’ and is associated with an increased incidence of other micro- and macrovascular complications, but it is not known whether it also plays a role in the pathogenesis of diabetic nephropathy. In fact, there are indications that hypertension plays only a secondary, although very important, role as recently reviewed by Deckert et aL4 This paper will present our present knowledge of the course of hypertension in IDDM patients developing nephropathy and, based upon this data, will discuss whether or not it has a primary role in the pathogenesis of diabetic nephropathy. In addition, a hypothesis of sodium-volume expansion causing hypertension in diabetic nephropathy will be discussed.
THE TIME COURSE
Reprint requests: Bo Feldt-Rasmussen, MD, DMSc, Steno Memorial Hospital, DK-2820 Gentofte, Denmark.
60
OF HYPERTENSION
Two studies indicate a predisposition to essential hypertension in IDDM patients who develop nephropathy. 5v6 The observations were, however, not confirmed in a Danish study comprising more probands and their parents than the previous studies.’ If there is no predisposition to hypertension, the question remains: When does this gradual rise in blood pressure begin? It is not present at onset of diabetes, because at that time, the blood pressure was normal in patients who later developed clinical nephropathy, and similar to that of patients who survived their disease for more than 40 years.6 The blood pressure is also normal in long-term IDDM patients with a urinary albumin excretion (UalbV) in the normal (~30 mg/24h) or slightly elevated (30-100 mg/24h) range.4 In contrast, a slight but significant elevation of blood pressure is present in IDDM patients with microalbuminuria.B-ll In these patients, we have observed a significant increase in diastolic blood pressure by serial blood pressure measurements over a 2 year prospective study period.12 The estimated annual increase in mean blood pressure was 2.7 mmHg, indicating a progression from normotensive to hypertensive levels within an 8 year period.12 The key question: Which comes first, increasing UalbV or blood pressure rise, seems to have been answered recently by Mathiesen et al.13 They followed 200 normotensive patients with IDDM and normal UalbV for 5 years. Fifteen patients developed persistent microalbuminuria without detectable changes in blood pressure until 1 or 2 years later. Therefore, a mechanism different from arterial hypertension must explain this increased transglomerular albumin escape.4 In further support of the hypothesis that an increase in blood pressure is not the primary event in the pathogenesis of diabetic nephropathy, we recently identified asubpopulation of IDDM patients with essential hypertension. The prevalence was similar to that of the background population. They all remained normoalbuminuric over the 4 years of observation (unpublished results). This demonstration of long-term hypertension without development of microalbuminuria or nephropathy, also supports the hypothesis that hypertension is, in fact, a secondary rather than primary event in the pathogenesis of diabetic nephropathy. This is not to deny the fact that hypertension has a deleterious effect on the progression of established diabetic renal disease (presence of persistent microalbuminuria).
HYPERTENSIONIN IDDM
61
kidney function in diabetic nephropathy. Br Med J 294:1443-
PATHOGENETIC MECHANISMS The pathophysiology of hypertension in diabetes is poorly understood. There is, at present, some evidence in favour of sodium-volume expansion playing a central role.14 Exchangeable sodium is elevated in normotensive IDDM as well as NIDDM patients free of microvascular complications,‘“16 was highest in patients with clinical nephropathy,16 and correlated with the mean blood pressure in a group of patients with microalbuminuria.14 The increase is accompanied by a concomittant increase in extracellular fluid volume (ECV).‘4,‘7,‘6 One group found the ECV increased only in patients with clinical nephropathy. lg Among the possible mechanisms for this sodium-provoked volume expansion are increased insulin-induced or glucose-coupled tubular reabsorption of sodium in the distal tubules, an effect of insulin which has been repeatedly demonstrated.2’t23 This was also demonstrated in a simple clinical set-up when an acute sodium load was retained in insulin treated (peripheral hyperinsulinemia) IDDM patients compared to normal controIs.24 The increased tubular reabsorption of sodium in IDDM patients with normal UalbV is also interesting in relation to the increased glomerular filtration rate (GFR) characteristic of these patients. According to the hypothesis of Leyssac, changes in GFR are secondary to alterations in the proximal tubular reabsorption rate of sodium and water.25 We have, therefore, hypothesized that the hyperfiltration of uncomplicated diabetes is secondary to insulin and/or glucose induced tubular reabsorption of sodium. Recent results are in favour of this hypothesis.22 We, therefore, speculated as to whether the blood pressure starts to increase in IDDM patients if the increased GFR, compensating for the sodium retention caused by peripheral hyperinsulinemia during insulin treatment, starts to decline.26 The pressor hormones will not be discussed in detail here, but there is much confusion in this field. At present, the catecholamines and renin-angiotensin-aldosterone system have not been proven to play any significant role.26
SUMMARY All IDDM patients without late complications have blood pressures similar to the nondiabetic background population, and those who develop clinical nephropathy in Denmark have no familial predisposition to hypertension. Blood pressure remains normal until after development of microalbuminuria, indicating no primary role for hypertension in the pathogenesis of nephropathy. When microalbuminuria is present it does, however, play a crucial role in the progression of nephropathy. Sodium retention, possibly induced by hyperinsulinemia, and perhaps glucose-coupled sodium reabsorption in insulin treated patients, seem to play a central role in elevating the blood pressure, but this needs further clarification.
REFERENCES 1. Major SG: Blood pressure in diabetes mellitus: A statistical study. Arch Intern Med 44:797-812,1929.
2. Parving H-H, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PAA: Effect of antihypertensive treatment on
1447,1987.
3. Drury PL: Diabetes and arterial hypertension. Diabetologia 24:19, 1983.
4. Deckerl T, Feldt-Rasmussen
5. 6.
7. 8. 9. 10. 11.
B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A: Albumin&a reflects widespread vascular damage. The Steno Hypothesis. Diabetologia 32:219-226, 1989. Viberti GC, Keen H, Wiseman M: Raised arterial pressure in parents of proteinuric insulin dependent diabetics. Br Med J 295515-517, 1987. Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti GC: Increased sodium-lithium countertransporl activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 3:146-l 50.1988. Norrgaard K, Jensen JS, Mathiesen ER, et al: Increased blood pressure and red cell sodium-lithium countertransport activity are not inherited in diabetic neohrooathv. Diabetes 38:15A, 1989. Feldt-Rasmussen 8, Borch-Johnsen K, Mathiesen ER: Hypertension in diabetes as related to nephropathy. Early blood pressure changes. Hweflension 7 fsuppl21:18-20. 1985. Mathiesen ER, Oxenball B, Johansen K, Svendsen PAA, Deckeri T: Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 26:40&410.1984. Christensen CK, Mogensen CE: The course of incipient diabetic nephropathy: Studies of albumin excretion and blood pressure. Diabetic Medicine 2:97-l 02. 1985. Wiseman M, Viberti GC, Mackintosh D, Jarrett RJ, Keen H: GlycaTmia, arterial pressure and micrpalbuminuria in type 1 (li;m&n-dependent) diabetes mellltus. D/abeto/ogfa 26:401-405,
12. FeldtlRasmussen B, Mathiesen ER, Decked T: Effect of two years of strict metabolic control on progression of incipient neohrooathv in insulin-deoendent diabetes. Lancet 11:130013b4 1’986: 13. Mathiesen ER, Rlann B, Jensen T, Storm B, Deckerl T: Microalbuminuria precedes elevation in blood pressure in diabetic nephropathy. Diabetolooia 31:519A, 1988. 14. Feldt-Rasmussen B, Mathiesen ER, Deckert T, et al: Central role for sodium in the pathogenesis of blood pressure changes independent of angtotensin, aldosterone and catecholamines in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30:61 O617,1987. 15. DeChatel R, Weidman P, Flammer J, et al: Sodium, renin, aldosterone, catecholamines and blood pressure in diabetes mellitus. Kidney Int 12:412421, 1977. 16. O’Hare JA, Ferris JB, Brady D, Twomey B, O’Sullivan DJ: Exchangeable sodium and renin in hypertensive diabetic patients with and without nephropathy. Hypertension 7 (suppl 2)X&48, 1985. 17. Fauchald P, Norseth J, Jervell J: Transcapillary colloid osmotic gradient, plasmavolume and interstitial fluid volume in long-term type 1 (insulin-dependent) diabetes. Diabetologia 28:269-273, 1985. 18. Briichner-Morlensen J: Glomerular filtration rate and extracellular fluid volumes during normoglycemia and moderate hyperglycemia in diabetics. Stand J C/in Lab /west 32:31 l-31 6. 1973. 19. Hommel E, Mathiesen ER, Giese J, Nielsen MD, Schiitten HJ, Parving H-H: On the pathogenesis of arterial blood pressure elevation early in the course of diabetic nephropathy. Stand J C/in Lab Invest 49:537-544, 1989. 20. Burg MB: Renal handling of sodium, chloride, water, amino acids and glucose. in Brenner BM, Rector FC, (eds), The Kidney, Philadelphia, W.B. Saunders, 328-370, 1981. 21. De Fronzo R: The effect of insulin on renal sodium metabolism. Diabetologia 21 :165-l 71, 1981. 22. NDrgaard K, Jensen T, Sktt P, et al: Volume expansion during hyperinsulinemia induces a parallel increase in glomerular filtration rate and lithium clearance in normal man. Diabetologia 32:523 A, 1989. 23. Skpltt P, Mathiesen ER, Hommel E, Gall MA, Bruun NE, Parving H-H: The increased proximal tubular reabsorption of sodium and
62
water is maintained in long-term insulin-dependent diabetics with early nephropathy. Stand J C/in Lab Invest 49:419-425,1989. 24. Roland JM, O’Hare JP, Walters G, Corral1 RJM: Sodium retention in response to saline infusion in uncomplicated diabetes mellitus. Diabetes Res 3:213-2151988. 25. Leyssac PP: The renin angiotensin system and kidney function. A
FELDT-RASMUSSEN ET AL.
review of contributions to a new theory. Acta Physiol Stand Suppl 442%52,1978. 28. Feldt-Rasmussen B: Microalbuminuria and clinical nephropathy in type 1 (insulin-dependent) diabetes mellitus: Pathophysiological mechanisms and intervention studies. (Thesis) Dan Med Bull 38:405-415,1989.