Review Article Drugs 17: 461-470 (1979) 00 12-6667 / 79/0600-0461 /$02.50/0 iCI ADIS Press Australasia Pty Ltd. AR rights re served.
Control of the Blood Glucose in Diabetes Mellitus: Is it Valuable? Is it Feasible? Rubin Bres sler Depanmant of Internal Medicine , Univefsity 01 ArizonlI. Tucson, Ari zona
Summary
The controversy over ....hether smcr blood glucose conlrol prevents or attenuates Ihe comp!icatir/rls of diabetes is slil! ,mr(/$l)ll'ed, bill the available dat a support the value of good blood glucose controf. The rewllilion of Ihe con{f(wersy is nOI feasi ble at present because ~f the com · plexity and fi oancial cost of a de{illilil'e nrosnecttve sludy and because ....e may not presen/ly possess pharmacological a~:r:nts ....hid , can accomplish the goal of fong term strict control of Ihe blood gluco.~e. Finally , hereas 11'1.' regard retinopalhy, nephropathy and neuropalhy as valid pathological endpoints, e are not secure in assuming that blood glucose represents the critical measurement for longitudinal assessment of metabolic control. St udies evaluating control based on blood and urine glucose assess ments are complicated by the failu re ~f the data to reRecl changes in minute til minute reJwlalion. TIllis. Ihe rekutve im;ensilivily of some of these parameters ofcomrol could accnnntforfaitures 10 demonstrate a corretauon ber....een adequacy of therapy and dio helic complications.
Controversy has existed for many years over the gain-risk aspects of rigid control of the blood glucose in patients with diabetes mellitus. The proponents of rigid control contend that correction of the metabolic abnormal ities of the diabetic state will delay or prevent the development of vascular complications (Bressler, 1978; Brownlee. 1978; Cah ill et al., 1976;
Keiding et al., 1952; Raskin, \978). Opponents of this thesis have raised a number of serious problems faced by patients and clinicians in the attainment of good blood glucose control (Bondy and Felig, 19 71 ; Knowles et al., 1965; Siperstein et al., 1977) and have questioned whether diabetic vascular complications are a consequence of the metabolic disorder or a
Control of Blood GkJeose in Diabet es
MeI~tus
separate and distinct manifestation of a disease state affecting both the blood glucose (metabolism) and the vascular system (Bondy and Felig, 1971: Bressler. 1978; Brownlee, 1978). The problems of diabetic control include: I) Patient errors in carrying out prescribed regimens (diet. activity. insulin dose. type and timing). 2) Testing of periodic urines and/ or occasional bloods are inadequate assessments of diabetic control. 3) Insulin schedules are fixed . whereas there is variability of activity and diet. Regimentation is difficult and imperfect (social-psychological problems). 4) Weapons for blood glucose control are inadequate. Insulin delivery systems are insensitive and crude. and as yet drugs are not available for control of gluconeogenesis (lipolysis. glucagon. growth hormone. proteolysis). 5) Dangerous hypoglycaemia with risks of mental deterioration. 6) Emotional problems deriving from the obligatory regimentation necessary for rigid blood glucose control. This results in socioeconomic problems in the adult and problems of family and peer group acceptance in the paediatric population.
I . l nvesugau ve Approaches to the Problem Opponents of rigid control consider that the University Group Diabetes Project (UGDP) has already shown that control of blood glucose does not afford protection against microvascular lesions. The 5 forms of therapy employed in this study failed to demonstrate any benefit of blood glucose control on microvascular lesions in adult non-insulin dependent patients. In these studies. subjects exhibited minimal initial hyperglycaemia and the blood glucose reductions achieved were small (Goldner et al., 1971; Siperstein et aI.• 1977). In recent years. a number of animal studies from several laboratories have shown that control of by-
462
perglycaemia in the diabetic rat. dog. monkey. bamster and mouse by means of insulin therapy or islet transplantation, prevents or minimises the formation of diabetic-like lesions in kidney. nerves and eye. Reviews of the natural history of diabetic vascular disease seen in patients at the Joslin Oink attest to a low complication rate among survivors of 40 years of the disease. Although 75 % of the insulin-dependent patients showed retinopathy only 50 % of them had severe proliferative retinopathy and only 8 % became blind. A similar result found in a survey in London confirms the low frequency of diabetic retinopathy as well as the small incidence of blindness IDclger, 1947: Hardin et al.• 1956; Keiding et al., 1952). The relationship of control to diabetic complications has focused on a number of areas. These include: I) Capillary membrane width in muscle. 2) Renal pathology. 3) Haemoglobin Ale and other intravascular factors. 4) Diabetic neuropathy. These areas will be discussed briefly. It has become evident from these studies that the pathological changes which are characteristic of diabetes mellitus in animals and humans may not be obligatory consequences of a genetic disease. The alterations of blood components and the renal pathological changes may be a result of poor control of an abnormal metabolic state; i.e. elevated levels of blood glucose. Evidence supporting this view exists (Bressler, 197 8; Brownlee. 1978; Raskin. 1978). However, the question of whether the metabolic control necessary is that of blood glucose, haemoglobin Ale. serum lipids. plasma glucagon. growth hormone. myoinositol. 2.3-diphosphoglyceric acid Irbc), blood viscosity. erythrocyte and/or platelet aggregation or other unkn own factors is still unanswered (Bressler. 197 8: Brownlee. \9 78). Although a number of these abnormalities have been returned towards normal with treatment. none has been causally related to the pathological changes of diabetes.
.., 1.1 Muscle Ca pillary Basement Membrane (MC BM) W idth The most dir ect controversy concerning the relations hip of control to microv ascular disease in humans centres on the several grou ps studying MCBM thickness. Siperstein and associates (Siperstein er a l., 1973) have foun d no relationship between the degree of blood glucose abn or mal ity. duration of the diabetic or prediabetic state and the width of the MCBM. Th eir findings are in direct conflict with Williamson's group (Willi amson et al., 1976) who found a high cor relation betw een MCBM width a nd duration of the disease. Th e influence of fixation a nd mo rph o met ric techniques o n muscle capillary base ment mem brane thickness in diabetes has been a centra) issue in this controvers y (Siperstein et al.. 197 )). Data from recent comparative studies appears to have resolved these tech nical questions (Williamson et al., 1976). Evaluation of stud ies. in the light of these new findings, supports the conclusion that muscle capillary basement membra ne thicke ning is related to the dura tion of decreased carbohydrate tolerance (Danowski and Sunder, 1972; Kilo et al., 1972 ; Pardo et al.•
1972). The relations hip between basement membrane thickening and the dura tion of overt diabetes mellitus has also been investigated in the renal glomerulus in a prospective study using biopsy material obtained from patients with juvenile diabetes (Osterby, 1974). Data from patients biopsied at the time of diagnosis and repeated I to 2 years later were compared with that from controls and juvenile diabetics w ith disease of 3.5 to 5 years duration. Us ing sophisticated statistical ana lyses of 500 to 2000 measurements per glomerulus. no significant differences were found between contr ols and diabetics at the onset of disease. Significant. but slight increases in capillary basement membrane (CBM) were found at repeat biopsy at I to 2 years. whereas greater thick.ening of CBM were seen in the 3.5 to 5 year biopsy specimens. These studies imply that huma n basement membrane morphology is nor mal at the onset of diabetes. and
only shows increased thickness after several years of abnormal metabolis m. However. concomitance does DOt pro ve causal ity. Tbe CBM and metabolic abnormal ities cou ld be separate and distinct manifestations of a genetic or non-genetic disorder.
1.2 Renal Pathology Information on the relationship of diabetic control to the renal pathology has derived from both animal and hum an studies (Bressler. 1978; Rask in. 19 78). Studies have been carried out in rats. monkeys and dogs. A lthough glomerular changes have been found in several of the diabetic animal models, the cnaracteristi c specific nodular lesion was lacking. Nodular lesions identical to those found in human diabetes have been found in dogs made diabetic by means of alloxan or growth horm one (Bloodwort h. 196$; Engerm an et al.. 1977; Raskin. 1978). Rats made diabetic by mea ns of alloxan or st reptozotoein develop intense linear staining of renal extracellula r membranes . These deposits of albumin. IgG. IgM and complement (C ,) have been demonstrated by immunohistochemical techniques (Mauer et al.• 1972; Miller. 1976). The character istic renal changes occurred after several months of hyperglycaemia and were found to be reversible. Renal tra nsplantation of kidneys of experimentally diabetic ra ts into non-diabetic recipients results. within 2 months in the disappearance of IgG , IgM and C, from the mesangium and the arrest or reversal of glomerular mesangial thickening (Lee et al., 1974). Conversely. transplantation of normal kidneys into diabetic recipients results in deposition of immu noglobulin and complement in the mcsang ium and visible mesangial thickening within 2 months (Lee et al.• 1974). Pancreatic islet transplantations in st reptozotocin diabetic rats. whose diabetes had been present for 6 to 8 months, resulted in a signifkant reduction in mesangial th ick.ening and in the mesangial staining for IgG. IgM and C J • These changes were apparent
Control of 8Iood Glucose in Diabetes Mellitus
two weeks after the restoration of normal blood glucose and insulin levels (Mauer et al., 1975). Evidence linking renovascular lesions in human diabetes to abnormal metabolism is impressive. Wh en non-diabetic human kidneys were transplanted into diabetics, characteristic diabetic renal pathology developed (Mauer et at, 1976a; Mauer et al.. 1976b). Serial yearly biopsies demonstrated the lesions within 2 to 3 years. The controlled study included baseline biopsies of the related donor kidney and serial biopsies from kidneys transplanted for diseases other than diabetes. It must be concluded from these studies that the abnormal diabetic environment was responsible for the development of diabetic renal pathology in transplanted kidneys which were genetically nondiabetic.
1.3 Haemoglobin AIC and Other Intravascular Factors The microvascular pathology of diabetes is frequent and fairly specific. This has led to studies on the abnormalities of intravascular factors in diabetics. Longitudinal assessment of these factors might serve as another index On addition to blood glucose) of metabolic control and/ or a prognostic guide. Some of the factors which have been studied include: (a) haemoglobin AIC and (b) platelet aggregation. Ha emoglobin At c is a minor haemoglobin component which was first characterised as a fast moving component on agar gel electrophoresis. A number of studies have shown that haemoglobin AIC is elevated in diabetics. Whereas , AIC comprises 3 to 6 % of the haemoglobin A of normals there is a 2- to 3-fold increase in diabetics (Paulsen and Kowry, \976; Rahbar , 1968). Moreover, a number of diabetic animal models, both genetic and non-genetic (alloxan), show elevations in AIC (Koenig and Cerami, 1975; Koenig et al., I976c). The rise in haemoglobin Ale seems to be a consequence of hyperglycaemia (Koenig et al. , \ 976a,b). The increase in haemoglobin AIC does not seem to be an inherited abnormality as it has been found to be
464
elevated only in the hyperglycaemic member of identical twins discordant for juvenile onset diabetes mellitus (Tettersat et al., 1975). Haemoglobin AIC is the product of the chemical condensation of haemoglobin and glucose. It differs from haemoglobin A due to the glucose moiety which is attached to the N-terminal amino group of the beta chain by a unique ketoamine linkage formed by a rearrangement of the Schiff base. It appears from the kinetic studies of Bunn et al. (\975, 1976) that the rate of formation of Hb Ale should be proportional to the time-averaged concentration of glucose within the erythrocyte. Thus, the level of Hb AIC could be a reflection of the adequacy of blood glucose control over a sustained period of time. Furthermore, the postsynthetic glycosylation of haemoglobin A in the diabetic may be representative of similar changes in other proteins which may occur during periods of sustained hyperglycaemia. The monitoring of Hb Ale may provide a better index of longitudinal blood glucose control and allow correlations with other pathological changes in the kidneys and nerves. Although no specific pathological effects of higher levels of haemoglobin AIC have been discerned, it has been shown that the release of oxygen from Hb AIC occurs less readily. Control of the blood glucose results in decreased levels ofHb AIC as shown by the studies of Koenig et al. (1976a,b). Platelet aggregation in diabetics has been found to be more sensitive to stimulation by a number of agents (ADP, adrenaline/epinephrine, collagen) than in normal subjects (Haloshka et al., 1977; Peterson et al., 1977; Preston et al., \9 78). This has been attributed to increased levels of plasma a-tbromboglobulin, and increased synthesis of PGE-Iike material (Haloshka et al., 1977; Preston et al., 1978). Institution of strict diabetic blood glucose control modified these abnormalities IHaloshka et al., 1977; Peterson et al., 1977; Preston et el., 1978). It is difficult to ascertain whether the increased platelet sensitivity to aggregating agents is causally related to microvascular disease. Moreover, the fibrinolytic system, which is a defense mechanism against platelet occlusion or microvasculature, has been found to be
46.
ContrOl 01 Blood Glucose in Dillbetn Mellit ...
decreased in diabetics (Fukuda. 1972; Paul and Adlakha . 1964). It still rem ains to be estab lished that these several intravascular abnormalities result in
diabetic microangiopathy ra ther than merely being consequences of the disease.
1.4 Diabetic Neu ropat hy A num ber of clinical neuropathological states have been described in diabetes. Alth ou gh segmental myelin degeneration is a characteristic lesion, impairment of the microvasculat ure supply of nerves has also been foun d. Decreased velocity of motor nerve conduction (VMNCl has been found in diabetic rats sho rtly after the onset of hyperglycaemia resulting fro m streotozotocin administration. Correction of the hyperglycaemia with insu lin therapy normalised the VMNC when therapy was institu ted soon after the onset of the hyperglycaemia. Stud ies in rats with chro nic diabetes have sho wn a correlatio n between the reduced VMNC and a diminished concentration of free myomcsitol in the nerves. Myoin05itol: is a major component of peripheral nerve which is supplied by diet. It has been found that gfucosuri c diabetic patients excrete a large fraction of dietary mvomcsnct whereas non -diabetics do not (Clements et al.. 19 74; G reene et at . 1975; W inegrad and Greene, 1975). Insulin therapy which ameliorated th e hyperglycaemia in streptozotocin-diabetic rats with ch ronic diabetes did not correct the impairment in VMNC, whereas dietary supplementation with myoinositol prevented the impairment of VMNC in the face of continued hyperglycaemia. This study suggests that hyperglycaemia resu lts in losses of myoinositol fro m nerve and that decreased neural myoinositol resu lts in diminished VMNC. Co rrect ion of the hypergtycaemia alone does not resto re the neural myoinositol: (Greene et at.• 1915 ; W inegrad and G reene. 1975 ). However. early therapy with insulin decreases loss of the myoinositol and prevents decreased VMNC from developing . Human studies are now in pro-
gress regard ing myoinositol balance an d VMNC (Clements, personal communication). Reduction of the VMNC has been found to be more marked in more poorly controIJed patients (G reene et at., 1975; Gregersen. 196 7; W inegrad and G reene. 1975).
2. Does Rigid Control ofthe Blood Glucose Delay or Prevent tne Complicationsof Diabetes? If control of blood glucose (metabol ic ab normal ities) was a critical aspect of the developm ent of m icrovascular, rena l and neuro logical lesions in diabetic patients. then it wou ld be expected that close control of the blood glucose wou ld delay or preven t these lesions . The problem is simple 10 form ulate but represen ts a complex and expensive solution. The complicatio ns of diabetes ta ke years to develop. wh ich means that any meaningful prospective stu dy wou ld entail in the order or 10 to 20 years of observation of a considerable populat ion of patients. Other formidable problems in a contem plated prospective st udy include the following considerations: I) Matched groups of subjects in regard to age. sex. duration of diabetes. weight. race. genetic history . and other diseases would be needed. 2) The groups would have to be contr olled for types of diabetic patho logy and the quan titative nature of this pathology. Blood glucose, urine glucose tests are neither complex nor expensive: however. fluorescein studies of the retina. VM NC studies. measurements of haemoglobin A Ie and urine myoinositol etc. may be expensive and complex. The need for renal biopsies is an open and di fficult question . 3) The most serious question of all which underlies the issue of whether rigid contro l of Ihe blood glucose changes the incidence and /or severity o f complications. is that of ou r ability to contro l the blood glucose at all with our current therapeutic: weapons . The factors involved in control of the blood glucose include:
Control of Blood Glucose in DlIlbel,"
M~us
I) Adequate amounts of insulin delivered at the tim e of glucose challenge. 2) Sensitivity to the insulin (endogenous or exogcnous). The labile or unstable (insu lin dependent) diabetic patient is in the main totall y dependent upon exogenous insulin for its anabolic and anticatabolic actions. Th e matching of injected insulin to ingested diet is at best an imperfect one and so the insuli n dependent patient experiences wide swings of blood glucose in the course of a day . Th e work of Molnar and ass ociates at the Ma yo Clinic have demonstrated thi s situation (Molna r et al.. 1972). However . recent studies utilising home monitoring of blood glucose as a gu ide to insulin therapy have demonst rated that good control was achieved in the majority of patients using conve ntional insulin regimens (Danowski et al., 1978 ; Sonkscn et al., 1978; Walford et al., 1978). No significant bypoglycaemia or other complications occu rred. This study suggests that an approach to normog lycaemia may be possible using conventional techno logy. It is clear that we do not possess as yet the ultimate means for 'physiological' control of blood glucose. Perhaps the advent of the pancreatic transplant, so ma tostatin type agents
Control of the Blood Glucose in Diabetes Mellitus: Is it Valuable? Is it Feasible? Rubin Bres sler Depanmant of Internal Medicine , Univefsity 01 ArizonlI. Tucson, Ari zona
Summary
The controversy over ....hether smcr blood glucose conlrol prevents or attenuates Ihe comp!icatir/rls of diabetes is slil! ,mr(/$l)ll'ed, bill the available dat a support the value of good blood glucose controf. The rewllilion of Ihe con{f(wersy is nOI feasi ble at present because ~f the com · plexity and fi oancial cost of a de{illilil'e nrosnecttve sludy and because ....e may not presen/ly possess pharmacological a~:r:nts ....hid , can accomplish the goal of fong term strict control of Ihe blood gluco.~e. Finally , hereas 11'1.' regard retinopalhy, nephropathy and neuropalhy as valid pathological endpoints, e are not secure in assuming that blood glucose represents the critical measurement for longitudinal assessment of metabolic control. St udies evaluating control based on blood and urine glucose assess ments are complicated by the failu re ~f the data to reRecl changes in minute til minute reJwlalion. TIllis. Ihe rekutve im;ensilivily of some of these parameters ofcomrol could accnnntforfaitures 10 demonstrate a corretauon ber....een adequacy of therapy and dio helic complications.
Controversy has existed for many years over the gain-risk aspects of rigid control of the blood glucose in patients with diabetes mellitus. The proponents of rigid control contend that correction of the metabolic abnormal ities of the diabetic state will delay or prevent the development of vascular complications (Bressler, 1978; Brownlee. 1978; Cah ill et al., 1976;
Keiding et al., 1952; Raskin, \978). Opponents of this thesis have raised a number of serious problems faced by patients and clinicians in the attainment of good blood glucose control (Bondy and Felig, 19 71 ; Knowles et al., 1965; Siperstein et al., 1977) and have questioned whether diabetic vascular complications are a consequence of the metabolic disorder or a
Control of Blood GkJeose in Diabet es
MeI~tus
separate and distinct manifestation of a disease state affecting both the blood glucose (metabolism) and the vascular system (Bondy and Felig, 1971: Bressler. 1978; Brownlee, 1978). The problems of diabetic control include: I) Patient errors in carrying out prescribed regimens (diet. activity. insulin dose. type and timing). 2) Testing of periodic urines and/ or occasional bloods are inadequate assessments of diabetic control. 3) Insulin schedules are fixed . whereas there is variability of activity and diet. Regimentation is difficult and imperfect (social-psychological problems). 4) Weapons for blood glucose control are inadequate. Insulin delivery systems are insensitive and crude. and as yet drugs are not available for control of gluconeogenesis (lipolysis. glucagon. growth hormone. proteolysis). 5) Dangerous hypoglycaemia with risks of mental deterioration. 6) Emotional problems deriving from the obligatory regimentation necessary for rigid blood glucose control. This results in socioeconomic problems in the adult and problems of family and peer group acceptance in the paediatric population.
I . l nvesugau ve Approaches to the Problem Opponents of rigid control consider that the University Group Diabetes Project (UGDP) has already shown that control of blood glucose does not afford protection against microvascular lesions. The 5 forms of therapy employed in this study failed to demonstrate any benefit of blood glucose control on microvascular lesions in adult non-insulin dependent patients. In these studies. subjects exhibited minimal initial hyperglycaemia and the blood glucose reductions achieved were small (Goldner et al., 1971; Siperstein et aI.• 1977). In recent years. a number of animal studies from several laboratories have shown that control of by-
462
perglycaemia in the diabetic rat. dog. monkey. bamster and mouse by means of insulin therapy or islet transplantation, prevents or minimises the formation of diabetic-like lesions in kidney. nerves and eye. Reviews of the natural history of diabetic vascular disease seen in patients at the Joslin Oink attest to a low complication rate among survivors of 40 years of the disease. Although 75 % of the insulin-dependent patients showed retinopathy only 50 % of them had severe proliferative retinopathy and only 8 % became blind. A similar result found in a survey in London confirms the low frequency of diabetic retinopathy as well as the small incidence of blindness IDclger, 1947: Hardin et al.• 1956; Keiding et al., 1952). The relationship of control to diabetic complications has focused on a number of areas. These include: I) Capillary membrane width in muscle. 2) Renal pathology. 3) Haemoglobin Ale and other intravascular factors. 4) Diabetic neuropathy. These areas will be discussed briefly. It has become evident from these studies that the pathological changes which are characteristic of diabetes mellitus in animals and humans may not be obligatory consequences of a genetic disease. The alterations of blood components and the renal pathological changes may be a result of poor control of an abnormal metabolic state; i.e. elevated levels of blood glucose. Evidence supporting this view exists (Bressler, 197 8; Brownlee. 1978; Raskin. 1978). However, the question of whether the metabolic control necessary is that of blood glucose, haemoglobin Ale. serum lipids. plasma glucagon. growth hormone. myoinositol. 2.3-diphosphoglyceric acid Irbc), blood viscosity. erythrocyte and/or platelet aggregation or other unkn own factors is still unanswered (Bressler. 197 8: Brownlee. \9 78). Although a number of these abnormalities have been returned towards normal with treatment. none has been causally related to the pathological changes of diabetes.
.., 1.1 Muscle Ca pillary Basement Membrane (MC BM) W idth The most dir ect controversy concerning the relations hip of control to microv ascular disease in humans centres on the several grou ps studying MCBM thickness. Siperstein and associates (Siperstein er a l., 1973) have foun d no relationship between the degree of blood glucose abn or mal ity. duration of the diabetic or prediabetic state and the width of the MCBM. Th eir findings are in direct conflict with Williamson's group (Willi amson et al., 1976) who found a high cor relation betw een MCBM width a nd duration of the disease. Th e influence of fixation a nd mo rph o met ric techniques o n muscle capillary base ment mem brane thickness in diabetes has been a centra) issue in this controvers y (Siperstein et al.. 197 )). Data from recent comparative studies appears to have resolved these tech nical questions (Williamson et al., 1976). Evaluation of stud ies. in the light of these new findings, supports the conclusion that muscle capillary basement membra ne thicke ning is related to the dura tion of decreased carbohydrate tolerance (Danowski and Sunder, 1972; Kilo et al., 1972 ; Pardo et al.•
1972). The relations hip between basement membrane thickening and the dura tion of overt diabetes mellitus has also been investigated in the renal glomerulus in a prospective study using biopsy material obtained from patients with juvenile diabetes (Osterby, 1974). Data from patients biopsied at the time of diagnosis and repeated I to 2 years later were compared with that from controls and juvenile diabetics w ith disease of 3.5 to 5 years duration. Us ing sophisticated statistical ana lyses of 500 to 2000 measurements per glomerulus. no significant differences were found between contr ols and diabetics at the onset of disease. Significant. but slight increases in capillary basement membrane (CBM) were found at repeat biopsy at I to 2 years. whereas greater thick.ening of CBM were seen in the 3.5 to 5 year biopsy specimens. These studies imply that huma n basement membrane morphology is nor mal at the onset of diabetes. and
only shows increased thickness after several years of abnormal metabolis m. However. concomitance does DOt pro ve causal ity. Tbe CBM and metabolic abnormal ities cou ld be separate and distinct manifestations of a genetic or non-genetic disorder.
1.2 Renal Pathology Information on the relationship of diabetic control to the renal pathology has derived from both animal and hum an studies (Bressler. 1978; Rask in. 19 78). Studies have been carried out in rats. monkeys and dogs. A lthough glomerular changes have been found in several of the diabetic animal models, the cnaracteristi c specific nodular lesion was lacking. Nodular lesions identical to those found in human diabetes have been found in dogs made diabetic by means of alloxan or growth horm one (Bloodwort h. 196$; Engerm an et al.. 1977; Raskin. 1978). Rats made diabetic by mea ns of alloxan or st reptozotoein develop intense linear staining of renal extracellula r membranes . These deposits of albumin. IgG. IgM and complement (C ,) have been demonstrated by immunohistochemical techniques (Mauer et al.• 1972; Miller. 1976). The character istic renal changes occurred after several months of hyperglycaemia and were found to be reversible. Renal tra nsplantation of kidneys of experimentally diabetic ra ts into non-diabetic recipients results. within 2 months in the disappearance of IgG , IgM and C, from the mesangium and the arrest or reversal of glomerular mesangial thickening (Lee et al., 1974). Conversely. transplantation of normal kidneys into diabetic recipients results in deposition of immu noglobulin and complement in the mcsang ium and visible mesangial thickening within 2 months (Lee et al.• 1974). Pancreatic islet transplantations in st reptozotocin diabetic rats. whose diabetes had been present for 6 to 8 months, resulted in a signifkant reduction in mesangial th ick.ening and in the mesangial staining for IgG. IgM and C J • These changes were apparent
Control of 8Iood Glucose in Diabetes Mellitus
two weeks after the restoration of normal blood glucose and insulin levels (Mauer et al., 1975). Evidence linking renovascular lesions in human diabetes to abnormal metabolism is impressive. Wh en non-diabetic human kidneys were transplanted into diabetics, characteristic diabetic renal pathology developed (Mauer et at, 1976a; Mauer et al.. 1976b). Serial yearly biopsies demonstrated the lesions within 2 to 3 years. The controlled study included baseline biopsies of the related donor kidney and serial biopsies from kidneys transplanted for diseases other than diabetes. It must be concluded from these studies that the abnormal diabetic environment was responsible for the development of diabetic renal pathology in transplanted kidneys which were genetically nondiabetic.
1.3 Haemoglobin AIC and Other Intravascular Factors The microvascular pathology of diabetes is frequent and fairly specific. This has led to studies on the abnormalities of intravascular factors in diabetics. Longitudinal assessment of these factors might serve as another index On addition to blood glucose) of metabolic control and/ or a prognostic guide. Some of the factors which have been studied include: (a) haemoglobin AIC and (b) platelet aggregation. Ha emoglobin At c is a minor haemoglobin component which was first characterised as a fast moving component on agar gel electrophoresis. A number of studies have shown that haemoglobin AIC is elevated in diabetics. Whereas , AIC comprises 3 to 6 % of the haemoglobin A of normals there is a 2- to 3-fold increase in diabetics (Paulsen and Kowry, \976; Rahbar , 1968). Moreover, a number of diabetic animal models, both genetic and non-genetic (alloxan), show elevations in AIC (Koenig and Cerami, 1975; Koenig et al., I976c). The rise in haemoglobin Ale seems to be a consequence of hyperglycaemia (Koenig et al. , \ 976a,b). The increase in haemoglobin AIC does not seem to be an inherited abnormality as it has been found to be
464
elevated only in the hyperglycaemic member of identical twins discordant for juvenile onset diabetes mellitus (Tettersat et al., 1975). Haemoglobin AIC is the product of the chemical condensation of haemoglobin and glucose. It differs from haemoglobin A due to the glucose moiety which is attached to the N-terminal amino group of the beta chain by a unique ketoamine linkage formed by a rearrangement of the Schiff base. It appears from the kinetic studies of Bunn et al. (\975, 1976) that the rate of formation of Hb Ale should be proportional to the time-averaged concentration of glucose within the erythrocyte. Thus, the level of Hb AIC could be a reflection of the adequacy of blood glucose control over a sustained period of time. Furthermore, the postsynthetic glycosylation of haemoglobin A in the diabetic may be representative of similar changes in other proteins which may occur during periods of sustained hyperglycaemia. The monitoring of Hb Ale may provide a better index of longitudinal blood glucose control and allow correlations with other pathological changes in the kidneys and nerves. Although no specific pathological effects of higher levels of haemoglobin AIC have been discerned, it has been shown that the release of oxygen from Hb AIC occurs less readily. Control of the blood glucose results in decreased levels ofHb AIC as shown by the studies of Koenig et al. (1976a,b). Platelet aggregation in diabetics has been found to be more sensitive to stimulation by a number of agents (ADP, adrenaline/epinephrine, collagen) than in normal subjects (Haloshka et al., 1977; Peterson et al., 1977; Preston et al., \9 78). This has been attributed to increased levels of plasma a-tbromboglobulin, and increased synthesis of PGE-Iike material (Haloshka et al., 1977; Preston et al., 1978). Institution of strict diabetic blood glucose control modified these abnormalities IHaloshka et al., 1977; Peterson et al., 1977; Preston et el., 1978). It is difficult to ascertain whether the increased platelet sensitivity to aggregating agents is causally related to microvascular disease. Moreover, the fibrinolytic system, which is a defense mechanism against platelet occlusion or microvasculature, has been found to be
46.
ContrOl 01 Blood Glucose in Dillbetn Mellit ...
decreased in diabetics (Fukuda. 1972; Paul and Adlakha . 1964). It still rem ains to be estab lished that these several intravascular abnormalities result in
diabetic microangiopathy ra ther than merely being consequences of the disease.
1.4 Diabetic Neu ropat hy A num ber of clinical neuropathological states have been described in diabetes. Alth ou gh segmental myelin degeneration is a characteristic lesion, impairment of the microvasculat ure supply of nerves has also been foun d. Decreased velocity of motor nerve conduction (VMNCl has been found in diabetic rats sho rtly after the onset of hyperglycaemia resulting fro m streotozotocin administration. Correction of the hyperglycaemia with insu lin therapy normalised the VMNC when therapy was institu ted soon after the onset of the hyperglycaemia. Stud ies in rats with chro nic diabetes have sho wn a correlatio n between the reduced VMNC and a diminished concentration of free myomcsitol in the nerves. Myoin05itol: is a major component of peripheral nerve which is supplied by diet. It has been found that gfucosuri c diabetic patients excrete a large fraction of dietary mvomcsnct whereas non -diabetics do not (Clements et al.. 19 74; G reene et at . 1975; W inegrad and Greene, 1975). Insulin therapy which ameliorated th e hyperglycaemia in streptozotocin-diabetic rats with ch ronic diabetes did not correct the impairment in VMNC, whereas dietary supplementation with myoinositol prevented the impairment of VMNC in the face of continued hyperglycaemia. This study suggests that hyperglycaemia resu lts in losses of myoinositol fro m nerve and that decreased neural myoinositol resu lts in diminished VMNC. Co rrect ion of the hypergtycaemia alone does not resto re the neural myoinositol: (Greene et at.• 1915 ; W inegrad and G reene. 1975 ). However. early therapy with insulin decreases loss of the myoinositol and prevents decreased VMNC from developing . Human studies are now in pro-
gress regard ing myoinositol balance an d VMNC (Clements, personal communication). Reduction of the VMNC has been found to be more marked in more poorly controIJed patients (G reene et at., 1975; Gregersen. 196 7; W inegrad and G reene. 1975).
2. Does Rigid Control ofthe Blood Glucose Delay or Prevent tne Complicationsof Diabetes? If control of blood glucose (metabol ic ab normal ities) was a critical aspect of the developm ent of m icrovascular, rena l and neuro logical lesions in diabetic patients. then it wou ld be expected that close control of the blood glucose wou ld delay or preven t these lesions . The problem is simple 10 form ulate but represen ts a complex and expensive solution. The complicatio ns of diabetes ta ke years to develop. wh ich means that any meaningful prospective stu dy wou ld entail in the order or 10 to 20 years of observation of a considerable populat ion of patients. Other formidable problems in a contem plated prospective st udy include the following considerations: I) Matched groups of subjects in regard to age. sex. duration of diabetes. weight. race. genetic history . and other diseases would be needed. 2) The groups would have to be contr olled for types of diabetic patho logy and the quan titative nature of this pathology. Blood glucose, urine glucose tests are neither complex nor expensive: however. fluorescein studies of the retina. VM NC studies. measurements of haemoglobin A Ie and urine myoinositol etc. may be expensive and complex. The need for renal biopsies is an open and di fficult question . 3) The most serious question of all which underlies the issue of whether rigid contro l of Ihe blood glucose changes the incidence and /or severity o f complications. is that of ou r ability to contro l the blood glucose at all with our current therapeutic: weapons . The factors involved in control of the blood glucose include:
Control of Blood Glucose in DlIlbel,"
M~us
I) Adequate amounts of insulin delivered at the tim e of glucose challenge. 2) Sensitivity to the insulin (endogenous or exogcnous). The labile or unstable (insu lin dependent) diabetic patient is in the main totall y dependent upon exogenous insulin for its anabolic and anticatabolic actions. Th e matching of injected insulin to ingested diet is at best an imperfect one and so the insuli n dependent patient experiences wide swings of blood glucose in the course of a day . Th e work of Molnar and ass ociates at the Ma yo Clinic have demonstrated thi s situation (Molna r et al.. 1972). However . recent studies utilising home monitoring of blood glucose as a gu ide to insulin therapy have demonst rated that good control was achieved in the majority of patients using conve ntional insulin regimens (Danowski et al., 1978 ; Sonkscn et al., 1978; Walford et al., 1978). No significant bypoglycaemia or other complications occu rred. This study suggests that an approach to normog lycaemia may be possible using conventional techno logy. It is clear that we do not possess as yet the ultimate means for 'physiological' control of blood glucose. Perhaps the advent of the pancreatic transplant, so ma tostatin type agents
