Octreotide

and Diabetes:

Theoretical

and Experimental

Aspects

H. Plrskov, A. Flyvbjerg, J. Frystyk, T. Ledet, N. Meller, S.E. Christensen, and A.G. Harris Diabetes is characterized by paradoxical hypersomatotropinemia and hyperglucagonemia. The latter appears to enhance the tendency in imperfect metabolic control to reduce nitrogen balance, and the former appears to accelerate the deterioration of carbohydrate and lipid metabolism, and also to induce peripheral insulin resistance and hyperinsulinemia. In addition to direct metabolic effects, increasing evidence points to an association between hypersomatotropinemia and a number of metabolically dependent, characteristic functional abnormalities linked to the development of late diabetic manifestations. These include increased capillary fragility, lipid and hemostatic aberrations, tissue hyperperfusion, including increased cardiac output and renal plasma flow, and kidney hypertrophy. In theory, octreotide’s actions could reduce these aberrations, and, in fact, this has been confirmed in recent experimental trials. Copyright 0 1992 by W. 8. Saunders Company

A

FUTURE ROLE FOR long-acting somatostatin analogues in the treatment of diabetes mellitus became apparent after the demonstration that constant intravenous (IV) infusion of native somatostatin reduces the elevated serum growth hormone (GH) and glucagon levels prevalent in (non-obese) insulin- and non-insulin-dependent diabetic (IDDM and NIDDM) patients, and that in IDDM, it reduces hyperglycemia.lm4 Since the hypothesis that GH has a causal role in diabetic angiopathy was first proposed in 1970,5 a continuing accumulation of evidence suggests that diabetic GH hyperproduction is harmful because it gives rise to vicious circles that tend to accelerate the development of metabolic aberrations and also late manifestations.6 Recent studies’ in human and experimental diabetes suggest that the role of GH in angiopathy may be mediated via insulin-like growth factor 1 (IGF-1). Octreotide (SandostatinQ) has now been used in several studies of metabolic, hormonal, and functional abnormalities in diabetic humans and the streptozotocin-diabetic rat. It has proven effective in increasing insulin sensitivity, as shown by the ability to reduce insulin administration by 30% to 50% in IDDM,8W9and in reducing circulating levels of GH and IGF-I.“,” Furthermore, octreotide, at least acutely, also reduces diabetic hyperglucagonemia. ” GH AND INTERMEDIARYMETABOLISM IN DIABETES

In nondiabetic humans, a single pulse of IV-injected GH, mimicking normal postprandial or nocturnal plasma peaks, induces an immediate reduction in muscular glucose uptake and, after approximately 2 hours, significant increases in serum ketone, glycerol, and free fatty acid (FFA) levels, pointing to augmented lipolysis. No effects on hepatic glucose production were noted. I3 Identical results were obtained in IDDM after a single, short-lived GH pulse (N. Msller, unpublished observations). Long-term, slight-to-moderate serum

From the Institute of Experimental Clinical Research, Aarhus Kommunehospital, Denmark; and the Division of Clinical Pharmacology, Cedars-Sinai Medical Center, Los Angeles, CA. Address reprint requests to H. Orskov, MD, Institute of Experimental Clinical Research, University ofAarhus Kommunehospitalet, 8000 Aarhus C, Denmark. Copyright 0 1992 by W.B. Saunders Company 0026-0495/92/4109-2024$03.00/O 66

GH elevation in nondiabetics does not induce discernible metabolic alterations, unless compensatory hyperinsulinemia is blocked by simultaneous IV somatostatin infusion.14 However, excessive GH administration (8 U twice daily) leading to an “acromegalic” elevation of serum IGF- 1 levels to approximately 800 pg/L did not induce a significantly higher basal blood glucose level, despite a doubled basal serum insulin level after 4 days’ treatment. I5 No detailed analysis of intermediary metabolism or degree of insulin resistance was made in this study. The sustained, often hugely elevated serum GH levels in acromegalic patients are usually wellcompensated in that the majority of patients have normal 24-hour blood glucose means. However, in-depth biochemical and kinetic evaluation with estimations of forearm metabolite exchange, respiratory quotients, hyperinsulinemic clamping, and hepatic glucose turnover show several indices of pronounced insulin resistance, all of which are completely normalized shortly after successful adenomectomy.” In well-controlled, C-peptide-negative diabetic patients without endogenous insulin reserves to combat hypersomatotropinemia, Press et al” demonstrated that GH administration, inducing average diurnal plasma levels comparable to or somewhat higher than those in ordinary to poor metabolic control, increased blood glucose levels after 18 hours by approximately lOO%, mainly through increased hepatic glucose production. In addition, blood ketone levels increased from 200 to 800 pmol/L and serum FFA levels increased by approximately 100%. Even a small residual endogenous insulin production is extremely important for restraining the rate of development of metabolic deterioration. Madsbad et al” showed in insulin-withdrawal experiments in two groups of IDDM patients (one of them C-peptide-negative but otherwise comparable) that increases in blood glucose, ketone, plasma cortisol, and GH levels were much steeper in the group without residual insulin secretion. The insulin-antagonistic effect of GH was also evident in the studies of Christiansen et alI9 demonstrating that elevation of serum GH levels in well-controlled, C-peptide-negative IDDM patients to levels seen in poor clinical control significantly increased kidney function, but it also necessitated a 70% increase in daily insulin supply to maintain unaltered glycemia. The insulin-antagonistic action of hypersomatotropinemia is extremely variable in other mammals, with the hypersensitive canine species at one extreme” and the rat at the other, with Metabolism. Vol41,

No 9, Suppl 2 (September), 1992: pp 66-71

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no deterioration of carbohydrate tolerance even in severely insulinopenic streptozotocin-diabetic animals.2’422 Hyperglucagonemia is another characteristic and paradoxical feature in diabetes mellitus.23 Although the general opinion is that it probably has little lasting effect on carbohydrate and lipid metabolism, in contrast to that of hypersomatotropinemia, a series of excellent studies by Almdal et al 24-27in the diabetic rat and in IDDM and NIDDM has strongly suggested that hyperglucagonemia may be a driving force in the tendency to decreased nitrogen balance in poor diabetic control through its accelerating effect on urea synthesis rate. Therefore, it would be advantageous to suppress both diabetic hyperglucagonemia and hypersomatotropinemia. In conclusion, nondiabetic humans are resistant to the diabetogenic actions of even severe hypersomatotropinemia and are capable in most cases, through compensatory hyperinsulinism, of largely overcoming the effect on carbohydrate metabolism and partly that on lipid metabolism. In contrast, insulinopenic diabetic humans are much more sensitive to GH, and increasingly so with decreasing endogenous insulin reserves. When exogenous insulin supplies are inadequate, the vicious circle of increasing serum GH levels and subsequent metabolic deterioration develops at a formidable rate. GH AND DIABETIC FUNCTIONAL AND VASCULAR

MANIFESTATIONS

Apart from the metabolic aberrations discussed above, certain functional abnormalities are characteristic, but not necessarily specific, for diabetes when it has not been perfectly controlled for some time. These abnormalities are clearly related to the degree of metabolic control and disappear or ameliorate when a strict diabetic regimen is imposed. They therefore cover the range from borderline normal to clearly abnormal values, just as do the elevated serum GH and reduced serum IGF- 1 levels. These characteristic, metabolically dependent trends toward (or overt) abnormalities include kidney hypertrophy and hyperfunction with increased renal plasma flow, glomerular filtration rate, and glomerular permeability for proteins’9.28‘33; decreased nerve-conduction velocity, concomitant with prolonged resistance against ischemia (the Steiness phenomenon) for nervous modalities carried by myelinated nerve fibers34335;certain coagulation parameters36.37 and certain lipid parameters3* that move in the direction believed to accelerate atherosclerosis-like vessel disease and to induce an augmented risk of thrombosis; increased blood perfusion of several tissues other than the kidney, including augmented cardiac output39; and increased capillary fragility.40 Some of these functional abnormalities, present in diabetes mellitus and in experimental diabetes, have been shown to recede or disappear after hypophysectomy and, later, with somatostatin or octreotide therapy or, inversely, to develop when GH is administered to nondiabetic or diabetic subjects. This has been observed for lipid deviations,4’ coagulation parameters, 8,42 increased cardiac output,43 capillary resistance,40.42 and also for kidney hypertrophy, hyperfunction, and glomerular hyperpermeability in diabetes mellitus”.‘9.44 and in streptozotocin diabetes in rats.45

The observations cited above concern the early metabolically dependent abnormalities that are then superimposed on late diabetic manifestations, eg, manifest diabetic nephropathy, the earliest hallmark of which is increased urinary albumin excretion,46 and retinopathy. There are indications that diabetic GH hyperproduction may be involved in the progression of microangiopathy. Lundbzek et a14’showed, in the first controlled clinical trial, that hypophysectomy delayed loss of vision in patients with retinopathy, and in a followup in more than 100 patients who had been treated 15 years before by pituitary yttrium implantation, Sharp et a14*reported that patients had fared significantly better than would have been expected according to their diabetes duration. Chateauneuf et a149demonstrated that in diabetic patients with nephropathy treated with octreotide for 6 months, albuminuria regressed or disappeared and, recently, Serri et al” also found that kidney hypertrophy and hyperfunction were reduced. Ledet and Vuust50,5’ noted that cultured aortic myomedial cells grew faster and produced more collagen after the addition of GH or after the addition of diabetic serum compared with normal serum, and that the effect disappeared when specific antibodies against GH were added: this gives experimental in vitro support for GH involvement in diabetic macroangiopathy. It has obviously been suspected, and recently evidence has been offered that these putative “proliferative” effects of GH are not direct, but are mediated via IGF- 1. IGF-1 AND DIABETIC FUNCTIONAL AND METABOLIC MANIFESTATIONS

There is a strong case for IGF-1 involvement in vascular growth and regeneration in general” and also for retinal vessels,53 and in pathophysiological situations with abnormal proliferation. Bornfeldt and Amqvist recently showed that constant infusion of IGF- 1 produced accelerated intimal regeneration in rats with arterial endothelial denudation.54 Under normal circumstances, IGF-1 expression in vessels is 10~~‘; however, an increase in blood flow or pressure leads very quickly to increased IGF- 1 immunostaining of smooth muscle cells in particular.55 Similarly, endothelial denudation in arteries induces IGF-1 immunoreactivity, first in invading endothelial cells and later in neointimal muscle cells.56 Furthermore, by immunostaining, transient expression of IGF1 is found during repair and development of capillaries, arteries, and veins,52 and in proliferating vascular cells in various autoimmune and inflammatory diseases.57,58As for diabetic retinopathy, the evidence is at present uncertain. Merimee et a159reported that serum IGF- 1 levels appeared to increase when retinopathy was accelerated. Sato et a16’supported this, and a prospective study by Hyer et al also indicated that an increase occurred when retinopathy accelerated.6’ However, most studies” suggest a decreased or low-normal serum IGF1 level in diabetics, regardless of the degree of late diabetic manifestations. Some studies have suggested that the transient deterioration of retinopathy occurring after transfer to intensive insulin treatment may be causally related to the concomitant increase in serum IGF-1 levels. A frequently cited study by Grant et al reported increased vitreous IGF- 1 content

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in patients undergoing vitrectomy for end-stage diabetic retinopathy.63 Some of the conflict in results and opinions is due to the problems in determining serum and tissue IGF levels by immunological or biological assays that are caused by the interference of binding proteins (six have now been characterized) and probably less than 1% of total IGF is circulating in the free form, and it is not certain whether these IGF-binding proteins are antagonistic or agonistic to IGF- 1 effects.” A role for IGF-1 in the development of manifest diabetic nephropathy is uncertain. However, there is increasing evidence that IGF-1 action is a prerequisite for the initiation of early diabetic kidney hypertrophy in rats, and that IGF- 1 is a renotrophic factor in this conditionb4 and in other conditions with rapid kidney growth.65 An accumulation of IGF-1 in the kidney tissue reaches its maximum level 24 to 48 hours after induction of experimental diabetes, and it regresses to normal within 4 days. The increase is linearly dependent on the degree of metabolic aberration, as is the degree of kidney hypertrophy. Both renal hypertrophy and IGF- 1 accumulation are prevented by strict metabolic control with insulin.64 In diabetic rats, octreotide administration is equally effective in this acute situation, but without interfering with the metabolic state45; additionally, after 6 months’ octreotide treatment, pronounced reductions in kidney tissue and serum IGF-1 levels were observed.66 The kidney hypertrophy and hyperfunction occurring at the onset of experimental and human diabetes and recurring during episodes of poor control may be related to the development of late diabetic nephropathy.” OCTREOTIDE

AND

DIABETIC

ABERRATIONS/MANIFESTATIONS

The rationale for using somatostatin or its analogues in the treatment of diabetes is to suppress hypersomatotropinemia and hyperghtcagonemia, to minimize their deleterious effects on carbohydrate, lipid, and protein metabolism and on the functional and vascular manifestations previously described. Somatostatin and octreotide also inhibit insulin secretion67368; however, this is of no therapeutic relevance in IDDM with several years’ diabetes duration, but it appears at first sight to be unfortunate in NIDDM with usually normal or high circulating insulin levels. Indeed, early studies with IV somatostatin infusion demonstrated that hyperglycemia increased in these patients. 69 However, the considerable proportion of NIDDM patients who do not respond adequately to diet and sulfonylurea after some length of treatment (secondary failures), and who therefore ought to be given insulin treatment, may benefit from octreotide treatment by improving control and reducing insulin resistance and hence peripheral insulinemia, a reduction that may lead to a delay in the development of atherosclerosis. The metabolic effects of native somatostatin in IDDM are evident from previous IV infusion studies in which a marked reduction in the insulin requirement to maintain unchanged glycemia was seen. Similarly. after octreotide, the insulin requirement is reduced by 25% to 50% in IDDM, also shown in long-term studies. 8.9 There have been conflicting reports about the efficacy of octreotide in reducing postprandial hy-

perglycemia. Some studies found pronounced reductions in blood glucose levels while others did not. However, the evidence is weak, as effects on blood glucose will obviously depend on the extent of residual P-cell function and on the reduction in insulin dosage. The therapeutic usefulness of octreotide in preventing the “dawn phenomenon” is as yet unproven. Although bedtime (10:00-l 1:00 PM) injection of octreotide was associated with significant reductions in blood glucose and GH levels for approximately 5 hours,” it failed to prevent early morning hyperglycemia. A slow-release formulation of somatostatin analogue or constant subcutaneous pump infusion may possibly achieve this goal. In vitro studies suggest inhibitory effects of octreotide on new vessel growth and endothehal cell replication.” Octreotide treatment has also been associated with improved visual acuity in patients with preproliferative diabetic retinopathy and macular edema.7’.73 Octreotide and angiopeptin, a somatostatin octapeptide analogue. also have inhibitory effects on myointimal proliferation and coronary transplant atherosclerosis74 and, furthermore, inhibit myointimal proliferation of rat carotid75 and rabbit femoral artery after angioplasty.76 It would be interesting to study local IGF-1 levels in these models of proliferative vessel disease with concomitant treatment with octreotide or angiopeptin. There are indications that octreotide may, independently of GH suppression, directly inhibit IGF- 1 formation and release at the hepatic level and also at other sites such as the kidney. Thus. Hyer et al’” and Serri et al” observed pronounced reductions in circulating IGF-I levels to hypopituitary levels in IDDM during long-term octreotide treatment with continuous subcutaneous pump infusion. despite only modest decreases in serum GH levels. Flyvbjerg et a14’ reported that octreotide administration to streptozotocin rats during the first 4 days of diabetes completely prevented the obligatory early increase in kidney IGF- 1 levels. In addition, serum IGF-1 levels were significantly decreased in the rats that received octreotide, pointing to a direct inhibitory effect on both hepatic IGF-1 release and kidney IGF-1 accumulation, when it is considered that GH secretion is almost nonexistent in poorly controlled diabetic rats.45 In long-term studies66 using octreotide treatment for 6 months in diabetic rats, serum IGF-1 levels were reduced to one half of those observed in untreated diabetic animals. In both diabetic and control animals, octreotide treatment also completely prevented the pronounced increase in urinary albumin levels with time. More conclusively as to a GH-independent inhibition of IGF- 1 synthesis and release, hypophysectomized rats on adequate exogenous GH administration exhibited pronounced reductions in IGF- 1 in serum and in other tissues in those groups also treated with octreotide.” Serri et al” showed that long-term octreotide treatment in IDDM reduces kidney size and function. Reduction in albuminuria has been reported by Chateauneuf et a1,49and other studies with native somatostatin” or octreotide” have demonstrated that both acutely reduce renal plasma flow and glomerular filtration rate in IDDM, probably by an immediate vascular effect. The abnormal coagulation and lipid profiles inducible in normal humans during exogenous GH administration4’ are similar to the aberrations found in lDDM36; in a recent study

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Norgaard et al reported that these abnormalities were reversible in IDDM patients on long-term octreotide treatment.* CONCLUSION

Studies have been reviewed demonstrating that diabetic hypersomatotropinemia and hyperghtcagonemia adversely affect intermediary metabolism in IDDM patients and also increase insulin resistance, necessitating greater insulin supplies and higher circulating insulin levels. Insulin resistance may itself be partly responsible for the early and increased atherosclerosis in these patients. Other studies demonstrate that some of the metabolically dependent functional aberrations prevalent in imperfectly controlled diabetes may be mimicked or augmented in both healthy and diabetic humans if serum GH levels are augmented. These aberrations have long been suspected to participate in or accelerate development of late diabetic vascular manifestations such as microangiopathy and macroangiopathy.

In theory, octreotide has excellent qualifications for reducing all of the adverse effects of hypersecretion of GH and glucagon, and clinical trials and animal experiments have demonstrated that it reduces insulin resistance, improves metabolism, and normalizes or ameliorates some of the functional abnormalities. Recent studies indicate that octreotide may also reduce manifest long-term diabetic microalbuminuria, an established omen of irreversible nephropathy. From the clinical studies, it is apparent that octreotide should be administered continuously, since with a two or three times daily injection scheme, GH and IGF-I suppression and metabolic improvement are inadequate, possibly due to rebound phenomena between injections. Hence, more delayed-release formulations of octreotide or even longer-acting new analogues are desirable. If somatostatin derivatives have a future place in trials or in the treatment of NIDDM, new analogues are required that lack insulin-suppressive effects.

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ET AL

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Octreotide and diabetes: theoretical and experimental aspects.

Diabetes is characterized by paradoxical hypersomatotropinemia and hyperglucagonemia. The latter appears to enhance the tendency in imperfect metaboli...
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