A mechanism by which primary or secondary hypothalamic involvement results in the development of insulin-dependent diabetes mellitus (IDDM)

J. theor. Biol. (1984) 111, 171-182

A Mechanism by which Primary or Secondary Hypothalamic Involvement Results in the Development of Insulin-dependent Diabetes Mellitus (IDDM) L. BRUCE WEEKLEY

Department of Zoology-Physiology, The University of Wyoming, Laramie, Wyoming 82071 U.S.A. (Received 2 March 1982, and in final form 14 June 1984) A literature survey and hypothesis is presented in which it is concluded that an intracellular ventromedial hypothalamic (VMH) glucopenia results in a bibrachial response consisting of adenohypophysial release of growth hormone and ACTH as well as sympathetic discharge, both of which act to elevate plasma glucose and remove the VMH glucopenia. This glucopenia may occur as a result of either a deficiency of circulating insulin or alterations in the kinetic properties of the VMH cellular insulin receptor. Two mechanisms for the development of insulin dependent diabetes mellitus (IDDM) are presented: (1) a defect in VMH glucose transport and/or metabolism such that a VMH glucopenia occurs with a subsequent bibrachial response. The result of this is glucose overproduction and a chronic excess glucose stimulus will eventually cause B-cell exhaustion (primary hypothalamic involvement). (2) reduction ofthe B-cell population by chemical, genetic and/or viral interactions with a consequential insulopenia results in a VMH glucopenia (secondary to a reduced glucose transport into the VMH cells) and causes a bibrachiai response. This VMH response may temporarily restore plasma glucose balance but a chronically enhanced counter-regulatory response to maintain this balance will eventually stress the remaining B-cell population and cause further reductions in B-cell numbers (secondary hypothaimic involvement).

Introduction Most workers in the field consider insulin-dependent diabetes mellitus ( I D D M ) to be not one but several diseases possibly with different causes and mechanisms of transmission. Metabolic studies now focus attention on the B-cells as the c o m m o n denominator and altered glucose metabolism as a cardinal feature of this disease. Insulin-dependent diabetes mellitus which is ascribed to a deficiency of insulin is thought to have several possible causes including a cellular autoimmune reaction against B-cells o f the pancreatic islets (Ledwig, Schernthaner & Mayr, 1979), genetic or viral interactions (Nerup, Anderson 171 0022--5193/84/210171 + 12 $03.00/0

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& Christy, 1976), direct chemical insult on the B-cells by diabetogenic drugs (Craighead, 1978) and enhanced sympathetic suppression of B-ceils (Weekley, 1981). However, a number of clinical studies have indicated that IDDM patients display signs of both altered autonomic and neuroendocrine function although whether this is primary or secondary to IDDM pathophysiology is not clear. Indeed, the maintenance of normal plasma glucose is accomplished in part by action of the autonomic nervous system and the neuroendocrine complex. The hypothalamus is involved in directing the functions of both and in the integration of their activity (Swanson & Sawchenko, 1980). It is the purpose of this review to address the pathophysiology of IDDM and present a possible mechanism by which altered hypothalamic function may be directly or secondarily involved in the etiology of IDDM.

Hypothalamic-insulin Interactions There is evidence that insulin acts directly on cells in the VMH to promote local glucose uptake (Debons, Krimsky & From, 1970) and metabolism (Panksepp, 1973), to alter electrical activity of those cells (Anand, et al., 1964; Oomura, 1973; Oomura et aL, 1974) and to stimulate norepinephrine release (McCaleb, 1972). The glucose analog gold thioglucose (GTG) is taken up by VMH cells in an insulin dependent manner (Debons et aL, 1970). Indeed, insulin receptors have been proposed to exist in the brain (Szabo & Szabo, 1975), and insulin has been reported to bind brain blood vessels throughout the CNS (Havrankova et al., 1978). Van Houten et al. (1979) has more recently described insulin receptors in brain which appear to be associated with the endothellum of cerebral capillaries located primarily in the hypothalamus, hippocampus and neocortex. Posner et al. (1974) reported that specific binding of ~25I-insulin to membrane preparations from monkeys was high in hypothalamic tissue while no appreciable binding occurred in cortical or thalamic preparations. The most intense insulin binding appears to be in the circumventricular organs (Van Houten et al., 1979) with the specific binding sites localized to nerve terminals in the median eminence and arcuate nucleus. These studies suggest that insulin, glucose or some interactio n of the two may modulate the activity of the VMH. These proposed VMH insulin receptors seem to influence B-cell activity since chronic intracerebroventricular insulin injection depresses plasma insulin in a dose dependent manner (Woods et al., 1979). On the other hand, both Storlien, Bellingham & Martin (1975) and Iguchi, Burleson & Szabo (1981) reported that microinjection of insulin into the VMH was effective in producing systemic hypoglycemia. However, Taborsky &

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Bermann (1980) found that intracerebroventricular injection of insulin+ 2-deoxy-D-glucose in dogs produced a rapid increase in peripheral insulin levels which was probably due to a CNS glucopenia; Davidson & Organ (1982) found that intracarotid injections of insulin does not alter plasma glucose in the rat although whether insulin injection per se will produce a CNS glucopenia is not clear, i.e. injection of insulin +2-deoxy-D-glucose may be a better way to produce a CNS glucopenia. Furthermore, systemic or intracerebroventricular injection of 2-deoxy-D-glucose results in feeding and hyperglycemia in rats (Misells & Epstein, 1975). Rowe et al. (1981) found that peripheral insulin infusion increases sympathetic nervous system activity as assessed by plasma norepinephrine and cardiovascular parameters, in the absence of changes in blood glucose. Furthermore, destruction of B-cells by streptozotocin or alloxan administration increases circulating levels of norepinephrine and increases norepinephrine turnover in sympathetically innervated tissue while not altering tissue norepinephrine levels (Kaul & Grewal, 1980). On the other hand, some preliminary data suggests that norepinephrine turnover in pancreas is depressed 10 weeks following streptozotocin treatment (Nadeau et al., 1983). Berkowitz et al. (1980) found that treatment with diabetogenic drugs increases circulating levels of norepinephrine and dopamine-/3-hydroxylase (increased Vmax) which can be prevented by transplantation of pancreatic islets (Schmidt, Nelson & Johnson, 1979), IDDM patients also have elevated plasma norepinephrine levels and the highest levels were found in diabetics who had not received insulin treatment (Christensen, 1974). It seems reasonable to assume that the increased sympathetic activity following induction of a chemical diabetes is due to a central nervous system glucopenia and the site of that glucopenia may be in the insulin sensitive areas of the hypothalamus (generally thought to be the VMH; sympathetic center). More recently, Ritter, Slusser & Stone (1981) have reported a hyperglycemic response to a cellular glucopenia in the hindbrain although whether this is an insulin sensitive site is not known; furthermore, the hormonal and/or autonomic changes producing this hyperglycemic response was not determined. Autonomic and Adrenal Medullary Regulation of Plasma Glucose Neural control of the endocrine pancreas has been well documented (Woods & Porte, 1976). Electrical stimulation of the ventromedial hypothalamus (VMH; sympathetic center) or splanchnic nerves inhibits insulin and augments glucagon release (Frohman, Bernardis & Stachura, 1974; Porte, 1969; Kaneto, Kajinuma & Kodaka, 1975). Miller, Waid & Joyce (1976) reported splanchnic nerve inhibition of insulin secretion in

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response to systemic hypoglycemia in dogs. Bloom (1976) reported hyperglucagonemia within t0 minutes following sptanchnic nerve stimulation in adrenalectomized calves and it was suggested that tonic sympathetic activity may be involved in minute to minute A-cell regulation. During the stimulation insulin levels remained unchanged in the face of hyperglycemia. Following stimulation insulin rebounded and was proportional to the degree of hyperglycemia. On the other hand, Rohner et al. (1977) reported that glucose stimulated insulin release (in vivo) was markedly elevated 10 minutes following bilateral electrolytic VMH lesions in rats and it was concluded that the VMH (sympathetic center) exerts an inhibitory influence upon the secretory activity of B-cells. Furthermore, this acute hyperinsulemia is reversed by subdiaphramatic vagotomy (Berthoud & Jeanrenaud, 1979). The rapidity of the insulin response to VMH lesions suggests that the VMH may be involved in minute to minute regulation of insulin secretion. Bergmann & Miller (1973) have shown that electrical stimulation of the lateral hypothalamus (LH; parasympathetic center), vagus (Kaneto, Kosaka & Nakao, 1967) or dorsal motor nucleus of the vagus (Inoescu et al., 1983) induces insulin secretion while Sakaguchi & Yamaguchi (1980) found that sympatho-adrenal release of catecholamines antagonizes vagal induced insulin release. Catecholamines may either inhibit or facilitate insulin release by stimulation of alpha or beta receptors respectively (Porte & Robertson, 1973; Woods & Porte, 1974; Basabe et al., 1977; Burr et al., 1974. Furthermore, there is also evidence which suggests that the sympathetic nervous system and adrenal medulla may be differentially activated under some metabolic conditions. For example, the rat treated with either phlorizin or 2-deoxy-Dglucose shows a marked stimulation of the adrenal medulla (i.e. release of epinephrine) while cardiac norepinephrine turnover is diminished (Landsberg et al., 1980; Rappaport, Young & Landsberg, 1982). These results suggest that sympathetic activity is altered in some tissues (presumably due to a VMH glucopenia) and occurs independently of adrenal medullary discharge. Indeed, Himsworth (1970) reported that LH glucopenia increases adrenal medullary secretion of epinephrine. Robinson, Culberson & Carmichael (1983) have found a number of sites in the cat hypothalamus which when stimulated will selectively increase norepinephrine or epinephrine secretion from the adrenal medulla. Furthermore, there is some older work which supports the view that epinephrine like substances are released from both the adrenal medulla and some other non-adrenal sources suring insulin-induced hypoglycemia (Armin & Grant, 1959; von Fuler, Ikkos & Luft, 1961).

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Diabetic patients with autonomic neuropathy have a blunted plasma epinephrine response to insulin-induced hypoglycemia (Bolli, Deteo & Compagnucci, 1983; Kleinbaum & Shamoon, 1983). This implies a role of the autonomic nervous system in the release of epinephrine during hypoglycemia, although the source of the epinephrine was not identified. Lesions of the VMH produce acute and chronic hyperinsulemia and proliferation of pancreatic B-cells while LH lesions depress blood insulin and decrease glucose tolerance (Martin, Konijnenijk & Bouman, 1974). On the basis of functional (Schlafani, Berner & Maul, 1973) and anatomic (Eager, Chi & Wolf, 1971) connections between the VMH and LH it has been postulated (Frohman & Bernardis, 1968) that VMH destruction might release vagal parasympathetic neurons resulting in enhanced insulin release irrespective of blood glucose levels. In fact, Kita et al. (1980), reported that electrical stimulation of the VMH inhibits vagal nerve activity while LH stimulation enhances vagal activity. It has been shown that the neural effects on the endocrine pancreas occur independently of its effect on gastrointestinal hormones which are known to affect pancreatic activity (Woods & Porte, 1976). The pituitary hormones also affect insulin secretion although this occurs independent of direct neural control. Hormonal Regulation of Blood Glucose by Glucagon Cryer (1981) suggested that glucagon plays a primary role in recovery from insulin-induced hypoglycemia and that a glucagon deficiency is largely compensated for by enhanced adrenomedullary epinephrine secretion. The acute release of ACTH (Plank, Bivens & Feldman, 1974) and/or growth hormone (DeFronzo et al., 1977) is not critical and sympathetic neural norepinephrine or adenohypophysial glucose autoregulation is not sufficient to promote complete glucose recovery from insulin-induced hypoglycemia. However, moderate physiological reductions of plasma glucose stimulates early increments in plasma epinephrine, norepinephrine and glucagon and later increments in plasma cortisol and growth hormone (Santeusanio et al., 1980). Furthermore, decrements from hyperglycemic to normoglycemic levels triggers a small response; decrements from high to low physiological levels triggers an intermediate response while decrements to severe hypoglycemic levels triggers a large hormonal response (DeFronzo, Hendler & Christensen, 1980): the magnitude of the hormonal counter-regulatory response is primarily an inverse function of the absolute plasma glucose concentration (Rosak et al., 1982). On the other hand, DeFronzo et al. (1977) found that a hormonal counter-regulatory response does not occur

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as long as plasma glucose concentration remains above fasting values. However, this situation does not seem to apply to patients with IDDM: a controlled decrement in plasma glucose causes a counter-regulatory response during a hyperglycemic period although glucagon levels did not change (DeFronzo et al., 1980). Furthermore, Zadik et al. (1980) reported that IDDM patients have increased plasma concentrations of norepinephfine, epinephrine, aldosterone and growth hormone while cortisol and plasma renin activity were not significantly different from controls. It seems possible that a change in the hypothalamic "glucostat" may be responsible for these changes (Weekley, 1981). In fact, Garcia et al. (1979) found differences in insulin binding to hypothalamic membranes following starvation and obesity, although a direct demonstration of altered hypothalamic sensitivity under various physiological conditions remains to be done. Hormonal Regulation of Blood Glucose by Growth of Hormone Lesions in the median eminence impair the growth hormone response to insulin induced hypoglycemia in monkeys (Abrams et al., 1966), while posterior hypothalamic lesions blunt the release of growth hormone following systemic 2-deoxy-o-glucose administration (Ferin et al., 1976). Reichlin (1970) and DeFronzo et al. (1977) have shown that the rate of fall of blood glucose is not the trigger of growth hormone release; the intracellular glucose level rather than the blood levels seem to be the determinant of growth hormone release since the inhibition of VMH glucose transport and/or metabolism by 2-deoxy-D-glucose causes growth hormone release in spite of systemic hyperglycemia in humans (Roth et al., 1964). The acute growth hormone release which occurs in response to insulin-induced hypoglycemia does not occur in animals with VMH lesions; conversely, local perfusion of the VMH region with glucose will inhibit the reflex secretion of growth hormone to systemic hypoglycemia or 2-deoxy-D-glucose administration (DeFronzo et al., t977). GTG lesions which specifically destroy insulin VMH cells result in impaired growth hormone secretion (Muller et al., 1971). These observations suggest that insulin sensitive VMH cells may mediate growth hormone release in response to cellular glucopenia. Molar et al. (1972) reported that at the time of growth hormone release, blood glucose levels were consistently higher in diabetics than in normal subjects. Indeed, I D D M patients often have elevated basal (Santeusano et al., 1980) and stimulated (Zadik et al., 1980) growth hormone levels and Hanssen (1974) suggested that defective glucose utilization in the hypothalamus, due to an absolute or relative insulin deficiency may result in an increased release of growth hormone.

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Hypothesis: Hypothalamic Involvement in Glucose Homeostasis The VMH, which is insulin sensitive, plays a regulatory role in both autonomic tone and pituitary hormone secretion. A decrease in VMH intracellular glucose results in a bibrachial response: (1) sympathetic discharge which acts to increase plasma glucagon levels and decrease plasma insulin levels which in turn increases plasma glucose levels. There is also some evidence which suggests that the adrenal medulla may respond to metabolic conditions independent of the sympathetic nervous system. (2) A pituitary response by releasing ACTH and growth hormone both of which alter systemic metabolism to increase plasma glucose. The increased glucose production then stimulates insulin release which in turn enhances peripheral and hypothalamic glucose transport and intracellular metabolism which acts to remove the stimulus for sympathetic discharge and hormone counterregulatory response (i.e. hypothalamic glucopenia) (see Fig. 1).

Hypothesis: Primary Hypothalamic Involvement in the Etiology of IDDM VMH glucopenia may occur secondarily to an alteration in VMH insulin receptors, glucose transport and/or intracellular metabolism, independent of initial changes in peripheral insulin levels. Baile, Herrara & Mayer (1970) have suggested that the VMH nucleus of o b / o b mice was not as sensitive to insulin as lean littermates. Furthermore, the observation that an inverse relationship between extracellular insulin concentration and the Bmax of both hypothalamic (Garcia et al., 1978) and peripheral tissues (Freychet et al., 1972) suggest that insulin receptors in the VMH may be of pathophysiological relevance. A defect in VMH insulin receptors such that a VMH glucopenia existed in the face of normal or even elevated plasma insulin and glucose levels, would result in a hormonal counter-regulatory response and sympathetic discharge. This would act to enhance glucagon secretion and glucose production while decreasing the insulin response to glucose. Furthermore, a chronic change in this hypothalamic "set point" would enhance baseline plasma glucose levels which would stress the B-cell population and eventually result in B-cell exhaustion. Any further decreases in plasma insulin only exacerbates the hypothalamic glucopenia which in turn further suppresses B-cell function and enhances A-cell function (see Fig. I).

Hypothesis: Secondary Hypothalamic Involvement in the Etiology of IDDM IDDM is due to an absolute or relative deficiency of insulin. Several possible causes of B-cell destruction have been proposed including a cellular autoimmune reaction against B-cells (Ludwig, Schernthaner & Mayr, 1979),

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FIG. 1. Proposed role of VMH in overall glucose metabolism. Intracellular VMH glucose levels acts as a sensor of peripheral tissue glucose utilization by virtue of its dependence on insulin. A VMH glucopenia results in a bibrachial response: (l) adenohypophysial release of growth hormone and ACTH which acts indirectly to elevate plasma glucose and (2) increased sympathetic and decreased parasympathetic activity which acts to increase plasma glucose. Furthermore, the adrenal medulla may respond independently of the sympathetic nervous system to metabolic stimuli. Increased plasma glucose then stimulates insulin release which facilitates glucose transport into peripheral and VMH tissue: this effect removes the initial stimulus (VMH glucopenia). Upper case lettering and heavy arrows indicates the site of the initial event in primary and secondary hypothalamic involvement. Primary hypothalamic involvement: reduced VMH glucose transport and/or metabolism ("set point") in the face of normal plasma glucose and insulin levels results in a VMH glucopenia. This VMH glucopenia triggers a bibrachial response which acts to increase plasma glucose and this increase serves to reduce the stimulus for the bibrachial response i.e. increased glucose stimulates insulin release which in turn decreases the degree of hypothalamic glucopenia. However, in order to keep the counter-regulatory response suppressed, increased plasma glucose and insulin levels are necessary. Maintenance of this chronic hyperglycemic-hyperinsulemic loop to suppress the hypothalamic counterregulatory response will eventually result in B-cell exhaustion and development of IDDM. Secondary hypothalamic involvement: a reduced B-cell population occurring as a result of direct B-cell insult by a cellular autoimmune reaction, chemical, genetic and/or viral interactions results in insulopenia, lnsulopenia depresses insulin mediated glucose transport and metabolism in the VMH cells which results in a bibrachial counter-regulatory response. This response elevates plasma glucose which stimulates insulin release and acts to remove the VMH glucopenia; elevated plasma glucose stresses the reduced B-cell population and may acutely return insulin to near normal levels. However, chronically elevated plasma glucose stresses B-cells and eventually will cause B-cell exhaustion. For details of the evidence for dual neurogenic innervation of the A- and B- cells presented in this figure (see Weekley, 1981).

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genetic or viral interactions with B-cells (Nerup, Anderson & Christy, 1976), chemical insult on the B-cells by diabetogenic drugs (Craighead, 1978) and enhanced sympathetic suppression of B-cells (Weekley, 1981). IDDM patients often have increased plasma levels of glucagon, growth hormone, ACTH and catecholamines all of which increase plasma glucose levels: hyperglycemia only exacerbates the IDDM condition by stressing the reduced B-cell population. VMH glucopenia produced as a result of decreased plasma insulin levels causes both the hormonal counter-regulatory response and sympathetic discharge. A continual hyperglycemic stress (due to reduced insulin levels concomitant with a hypothalamic and autonomic counter-regulatory response) in the face of a reduced B-cell population would acutely reduce the insulin response to glucose and chronically would cause further exhaustion of the B-cells: this chronic effect would eventually cause further insulopenia and hence hyperglycemia which in turn further reduces the B-cell population. Chemical destruction of B-cells has in fact been reported to cause sympathetic discharge (Berkowitz et al., 1980) as well as a hormonal counter-regulatory response and it seems likely that these effects occur secondary to a VMH glucopenia as a result of insulin deficiency (Rosak et aL, 1982). A compensatory decrease of glucagon or growth hormone if it occurred might improve diabetic hyperglycemia and remove a chronic stress on the B-cells. However, the diabetic state is characterized by increased plasma levels of these hormones and this represents an attempt by the VMH to remove intracellular glucopenia. In fact, VMH lesions at least partially reverse streptozotocin-induced IDDM in rats (Goldman et al., 1972) and in genetically diabetic mice (Coleman & Hummel, 1970). Furthermore, islet isografts in rats with streptozotocin-induced diabetes reverses the IDDM, but there is abnormal glucose tolerance and eventual exhaustion of the transplanted cells pointing to the important role of autonomic innervation of islets in maintenance of endocrine pancreatic function (Vialettes et al., 1979). Both adrenalectomy and hypophysectomy are known to reduce the severity of I D D M (Debons et al., 1979) and this effect is probably due to a reduction in endogenous glucose production and the removal of circulating insulin receptor antagonists. This points to the negative effect that chronically elevated plasma glucose and circulating insulin antagonists plays in the pathophysiology of IDDM (see Fig. 1).

IDDM: Similarity to Feeding Behavior It is interesting to speculate that this VMH glucopenia may be similar to the metabolic condition which occurs during fasting in which there are

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relatively minor changes in VMH glucose. However, during a fast there seems to be a reduction in sympathetic activity presumably mediated by a central mechanism while a concomitant increase in adrenal medullary activity occurs. Since the adrenal medulla is innervated by sympathetic nerve terminals and it is likely that non-homogenous sympathetic outflow to various organs occur, it seems reasonable to suggest that these two independent responses may be mediated by a central mechanism. Indeed, on the basis of electrophysiological studies Marrazzi (1976) suggested that VMH cells have a range of thresholds to circulating glucose and it seems reasonable to propose that this differential sensitivity may cause nonhomogeneous sympathetic outflow to the pancreatic islets and adrenal medulla although it is also possible that the adrenal medulla may be responding directly to an altered peripheral metabolic stimuli. However, one fundamental difference between the metabolic response to fasting and this proposed etiologic mechanism for development of IDDM lies in the fact that during fasting changes in plasma insulin and autoregulation of its receptor are within normal physiological ranges while long term reductions in circulating insulin as a result of chemical, genetic and/or viral interactions with the pancreatic islets (secondary hypothalamic involvement) are chronic and insulin levels are pathophysiological (at least in the advanced stages of the disease). Furthermore, it is possible that VMH glucose transport and/or metabolism (primary hypothalamic involvement) may change independent of the normal mechanisms regulating the hormone receptor (which is what presumably occurs during a fast) and hence result in a cascade of metabolic events eventually resulting in the development of IDDM. Although the response to fasting and this etiologic mechanism may be qualitatively similar, it seems reasonable to suggest that they are quantitatively different and hence some of the manifestations of IDDM are different. REFERENCES ABRAMS, R., PARKER, M., BANCO, S., REICHLIN, S. & DAUGHADAY, W. (1966). Endocrinol. 78, 605. ANAND, B., CHHINA, G., SHAR.MA,K., DUA, S. & SlNGH, B. (1964). Am. J. Physiol. 207, 1146. ARMIN, J. & GRANT, R. (1959). J. Physiol. 149, 228. BAILE, C., HER.RARA, M. & MAYER., J. (1970). Am. J. Physiol. 218, 857. BASABE, J., FARINA, J., UDR.ISAR, D. & CHIERI, R. (1977). Horm. Metab. Res. 9, 108. BERGMANN, R. N. & MILLER., R. E. (1973). Ant J. Physiol. 228, 181. BER.KOWITZ, B., HEAD, R., JOH, T. & HEMPSTEAD, J. (1980). J. pharmacol. Expt. Therap. 213, 18. BERTHOUD, H. R. 8:. JEANR.ENAUD, B. (1979). Endocrinology 105, 146. BLOOM, S. (1976). Hornt Metab. Res. Suppl. 6, 85. BOLLI, G., DEFEO, P. & COMPAGNUCCI, P. (1983). Diabetes 32, 134.

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