The Beaver Dam Eye Study. Retinopathy in adults with newly discovered and previously diagnosed diabetes mellitus.

During the last decade, the GH axis has become the compelling focus of remarkably active and broad-ranging basic and clinical research. Molecular and genetic models, the discovery of human GHRH and its receptor, the cloning of the GHRP receptor, and the clinical availability of recombinant GH and IGF-I have allowed surprisingly rapid advances in our knowledge of the neuroregulation of the GH-IGF-I axis in many pathophysiological contexts. The complexity of the GHRH/somatostatin-GH-IGF-I axis thus commends itself to more formalized modeling (154, 155), since the multivalent feedback-control activities are difficult to assimilate fully on an intuitive scale. Understanding the dynamic neuroendocrine mechanisms that direct the pulsatile secretion of this fundamental growth-promoting and metabolic hormone remains a critical goal, the realization of which is challenged by the exponentially accumulating matrix of experimental and clinical data in this arena. To the above end, we review here the pathophysiology of the GHRH somatostatin-GH-IGF-I feedback axis consisting of corresponding key neurotransmitters, neuromodulators, and metabolic effectors, and their cloned receptors and signaling pathways. We propose that this system is best viewed as a multivalent feedback network that is exquisitely sensitive to an array of neuroregulators and environmental stressors and genetic restraints. Feedback and feedforward mechanisms acting within the intact somatotropic axis mediate homeostatic control throughout the human lifetime and are disrupted in disease. Novel effectors of the GH axis, such as GHRPs, also offer promise as investigative probes and possible therapeutic agents. Further understanding of the mechanisms of GH neuroregulation will likely allow development of progressively more specific molecular and clinical tools for the diagnosis and treatment of various conditions in which GH secretion is regulated abnormally. Thus, we predict that unexpected and enriching insights in the domain of the neuroendocrine pathophysiology of the GH axis are likely be achieved in the succeeding decades of basic and clinical research.

Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human

In evolutionary terms, GH and intracellular STAT 5 signaling is a very old regulatory system. Whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress and fasting. GH exerts anabolic effects directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When subjects are well nourished, the GH-induced stimulation of IGF-I and insulin is important for anabolic storage and growth of lean body mass (LBM), adipose tissue, and glycogen reserves. During fasting and other catabolic states, GH predominantly stimulates the release and oxidation of FFA, which leads to decreased glucose and protein oxidation and preservation of LBM and glycogen stores. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the basal state, the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress, the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50%, with a similar increase in muscle protein breakdown. GH is a counterregulatory hormone that antagonizes the hepatic and peripheral effects of insulin on glucose metabolism via mechanisms involving the concomitant increase in FFA flux and uptake. This ability of GH to induce insulin resistance is significant for the defense against hypoglycemia, for the development of "stress" diabetes during fasting and inflammatory illness, and perhaps for the "Dawn" phenomenon (the increase in insulin requirements in the early morning hours). Adult patients with GH deficiency are insulin resistant-probably related to increased adiposity, reduced LBM, and impaired physical performance-which temporarily worsens when GH treatment is initiated. Conversely, despite increased LBM and decreased fat mass, patients with acromegaly are consistently insulin resistant and become more sensitive after appropriate treatment.

Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects.

Immunohistochemical evidence for separate populations of somatostatin-containing and substance P-containing primary afferent neurons in the rat.

Recent epidemiologic studies have suggested that cardiac disease in common in diabetics and may often have a noncoronary basis. To examine the status of the left ventricle, 17 adult-onset diabetics of familial type without hypertension or obesity underwent hemodynamic study and were compared to 9 controls of similar age.

Of the 17, 12 subjects had no significant occlusive lesions by coronary angiography. From this group eight without heart failure had a modest, but significant, elevation of left ventricular end-diastolic pressure. End-diastolic and stroke volumes were reduced, but ejection fraction and mean rate of fiber shortening were within normal limits. The left ventricular end-diastolic pressure/volume ratio was significantly higher than controls. Afterload increments effected a significant increase of filling pressure compared to normals without a stroke volume response, consistent with a preclinical cardiomyopathy. Four patients with prior heart failure had similar but more extensive abnormalities. None had local dyskinesia by angiography, and lactate production was not observed during pacing-induced tachycardia. Left ventricular biopsy in two patients without ventricular decompensation showed interstitial collagen deposition with relatively normal muscle cells. These findings suggest a myopathic process without ischemia.

Postmortem studies were performed in 11 uncomplicated diabetics. Nine were without significant obstructive disease of the proximal coronary arteries, and the majority succumbed with cardiac failure. On left ventricular sections, none had evident luminal narrowing of the intramural vessels. All nine exhibited periodic acid-Schiff-positive material in the interstitium. Collagen accumulation was present in perivascular loci, between myofibers, or as replacement fibrosis. Multiple samples of left ventricle and septum revealed enhanced triglyceride and cholesterol concentrations, as compared to controls. Thus, a diffuse extravascular abnormality may be a basis for cardiomyopathic features in diabetes.

/pdf/evidence-for-cardiomyopathy-in-familial-diabetes-mellitus-2gq529sgte.pdf

Evidence for Cardiomyopathy in Familial Diabetes Mellitus

Inhibition of insulin secretion by somatostatin

Diabetes, diabetic angiopathy, and growth hormone.

Muscle biopsies were studied from sixteen juvenile, long-term diabetics. Most of the patients had severe retinopathy, but clinical signs of other forms of angiopathy and neuropathy were either absent or mild. The biopsies revealed severe degeneration, as well as ineffective regenerative changes of the terminal nerve fibres and endorgans.

/pdf/pathological-changes-in-the-central-and-peripheral-nervous-16y4ceoni2.pdf

Pathological changes in the central and peripheral nervous system of young long-term diabetics

A study of the clinical observations and the neuropathological findings in the brain of 16 juvenile diabetics dying of diabetic angiopathy after many years of diabetes is presented. A characteristic histological pattern was observed in all the cases consisting of diffuse degenerative abnormalities of the brain tissue, often with severe pseudocalcinosis or with atrophy of the dentate nucleus, demyelinisation of the cranial nerves, fibrosis of the leptomeninges and angiopathy. The degenerative changes were so pronounced that a dual pathogenesis seems likely; viz. an ischemia caused by the angiopathy and a primary diabetic abnormality of the brain tissue. The clinical symptoms of cerebral disease varied from insignificant to pronounced. A correlation was found between the symptoms and the number of areas of softening in the brain. The histological pattern differs from that seen in other clinical conditions and justifies the term diabetic encephalopathy.

/pdf/pathological-changes-in-the-central-and-peripheral-nervous-3yfx5ixnze.pdf

Knud Lundbæk

Papers

Inhibition of insulin secretion by somatostatin

Diabetes, diabetic angiopathy, and growth hormone.

Pathological changes in the central and peripheral nervous system of young long-term diabetics

Pathological changes in the central and peripheral nervous system of young long-term diabetics : I. Diabetic encephalopathy.

Diabetic angiopathy: a specific vascular disease.