Gareth Williams

Increased neuropeptide Y concentrations in specific hypothalamic regions of streptozocin-induced diabetic rats

Untreated streptozocin-induced diabetic (STZ-D) rats have previously been shown to have significantly increased hypothalamic concentrations of neuropeptide Y (NPY), a regulatory peptide that powerfully stimulates eating and drinking and inhibits secretion of several pituitary hormones when injected centrally. Tissue NPY concentrations have been measured by radioimmunoassay in selected hypothalamic regions microdissected from fresh, unfixed brain slices to localize diabetes-associated NPY changes precisely within the hypothalamus. Significant (35–200%) increases in NPY concentrations (P < .01 vs. matched nondiabetic controls) were found in specific hypothalamic regions between 3 and 14 wk after induction of STZ-D. These regions included the paraventricular and ventromedial nuclei and lateral hypothalamic area, major appetite-regulating areas that are sensitive to the hyperphagic and polydipsic actions of NPY. Increased NPYergic activity in these areas may, at least partly, drive the increased eating and drinking characteristic of STZ-D. NPY concentrations were also increased in the arcuate nucleus and medial preoptic area. Because both of these regions are important in modulating pituitary hormone secretion, local NPY increases may be involved in the impaired secretion of luteinizing hormone, thyroid-stimulating hormone, growth hormone, and prolactin known to occur in STZ-D. Our finding of NPY increases in specific hypothalamic nuclei associated with functional changes found in STZ-D suggests that this peptide may have a role in the altered metabolic and neuroendocrine regulation of the syndrome.

Increased Hypothalamic Neuropeptide Y Concentrations in Diabetic Rat

Central and lateral hypothalamic concentrations of 10 regulatory peptides were measured by radioimmunoassay in streptozocin-induced diabetic (STZ-D) and matched control rats between 1 day and 14 wk after diabetes induction. After 2 wk, both central and lateral hypothalamic neuropeptide Y (NPY) concentrations in STZ-D rats were consistently higher than those found in control rats, with significant 30–50% increases at 4 wk in the central hypothalamus, and at 6 and 14 wk in both central and lateral hypothalamus. Immunocytochemical studies in 4- and 6-wk STZ-D animals showed the appearance of intensely NPY-positive swollen cell bodies in the supraoptic nucleus and a subjective increase in NPY staining of medial hypothalamic nerve fibers. Central hypothalamic concentrations of three other peptides were significantly greater in STZ-D animals than those in control animals at single points (neurotensin, 1 day; calcitonin gene-related peptide, 2 wk; neurokinin, 4 wk). Hypothalamic concentrations of the other six peptides examined (bombesin, galanin, neuromedin B, substance P, somatostatin, and vasoactive intestinal peptide) did not differ significantly between STZ-D and control groups at any time. However, galanin immunostaining in the supraoptic and magnocellular paraventricular nuclei was strikingly concentrated in a reduced number of distended cell bodies. Hypothalamic peptide changes in STZ-D could be related to metabolic disturbance, changes in energy and water balance, altered pituitary function, or other factors. Persistently elevated concentrations of NPY, a very potent central stimulant of eating and drinking, may mediate the hyperphagia and polydipsia characteristic of STZ-D.

Hyperglycaemic crises and lactic acidosis in diabetes mellitus

Diabetic ketoacidosis, hyperglycaemic hyperosmolar state, and lactic acidosis represent three of the most serious acute complications of diabetes. There have been some advances in our understanding of the pathogenesis of these conditions over the last three decades, together with more uniform agreement on their treatment and innovations in technology. Accordingly their incidence, morbidity, and mortality are decreasing, but at rates that fall short of our aspirations. Hyperglycaemic crises in particular remain an important cause of morbidity and mortality in diabetic populations around the world. In this article, understanding of these conditions and advances in their management, and the available guidelines for their treatment, are reviewed. As far as is possible, the recommendations are based on clear published evidence; failing that, what is considered to be a common sense synthesis of consensus guidelines and recommendations is provided.

Reform of undergraduate medical teaching in the United Kingdom: a triumph of evangelism over common sense

There is an urgent need to test whether the current reforms in training of doctors are the right answer to the shortcomings of traditional training

The prediction of diabetic neuropathic plantar foot ulceration by liquid-crystal contact thermography

OBJECTIVE To assess whether the development of plantar foot ulceration could be predicted from the mean plantar foot temperature (MFT), as assessed by liquid-crystal contact thermography (LCT), in patients with peripheral neuropathy. RESEARCH DESIGN AND METHODS Fifty patients with painful diabetic sensorimotor neuropathy were studied prospectively. Initially, 30 patients had no significant peripheral vascular disease (PVD) (ankle:brachial systolic blood pressure ratio >1.0). LCT was used to assess the MFT from eight standard plantar sites. RESULTS Initial MFT was higher in the patients without PVD (28.2 ± 2.9°C, mean ± SD) than in patients with PVD (25.6 ± 1.9°C, P < 0.001) and in nondiabetic control subjects (25.7 ± 2.1°C, P < 0.001). At review, on average 3.6 (range 3.0–4.1) years later, 11 patients had died (6 of whom had PVD), and one was lost to follow-up. Six patients (seven feet) from the group without PVD had developed neuropathic plantar foot ulcers. The initial MFT was significantly higher in these seven feet (30.5 ± 2.6°C) than in the 38 feet of the 19 survivors in this group (27.8 ± 2.3°C, P < 0.01). Only one patient with PVD developed a plantar ulcer, although four required foot surgery for ischemie feet. CONCLUSIONS LCT is a simple, inexpensive, and noninvasive method of identifying the neuropathic foot at increased risk of ulceration. Patients with high plantar foot temperatures are at increased risk of neuropathic foot ulceration. A normal or low MFT in the neuropathic foot is a marker of PVD, which confers an increased risk of ischemie foot disease.

Orexins and the treatment of obesity

Orexin-A and -B are two peptides derived by proteolytic cleavage from a 130-amino acid precursor, prepro-orexin, which were recently isolated from the rat hypothalamus. Orexin-A is fully conserved across mammalian species, whilst rat and human orexin-B differ by two amino acids. These peptides bind to two Gq-coupled receptors, termed orexin-1 and orexin-2. The receptors are 64% homologous and highly conserved across species. Orexin-A is equipotent at orexin-1 and orexin-2 receptors, whilst orexin-B displays moderate (approximately 10 fold) selectivity for orexin-2 receptors. The distribution and pharmacology of the orexin peptides and their receptors indicate that they play a role in various regulatory systems including energy homeostasis and the regulation of feeding, the evidence for which is reviewed here.

Withdrawal of sibutramine in Europe

Another sign that there is no magic bullet to treat obesity

Clinical Features of Brittle Diabetic Patients Unresponsive to Optimized Subcutaneous Insulin Therapy (Continuous Subcutaneous Insulin Infusion)

We examined the clinical features of 14 brittle diabetic patients, all of whom had failed to achieve near-normoglycemia during the ordinarily optimal treatment regimen of continuous subcutaneous insulin infusion. All patients were female. Seven patients had obvious family problems such as divorce or parental conflict. Type A (12 patients) suffered mainly from frequent, unpredictable episodes of ketoacidosis, necessitating many emergency admissions to a hospital; type B (two patients) complained of frequent, unpredictable, symptomatic hypoglycemia, short of coma and not requiring admission to a hospital. Type A brittle diabetic individuals were compared with 12 stable diabetic patients matched for age, sex, and duration of diabetes. The type A diabetic patients were young (mean age: 19.2 yr; range: 13–27 yr) with a wide range of duration of diabetes (2.5–23 yr) and brittleness (1–11 yr). Although their body mass index (BMI) was not significantly different from the stable diabetic subjects, many type A brittle patients were overweight, despite usually constant ketosis and hyperglycemia. The daily subcutaneous insulin dose was significantly higher than for stable diabetic individuals (mean ± SEM: 7.1 ± 2.6 versus 0.96 ± 0.12 U/kg), reflecting, perhaps, a subcutaneous absorption barrier in brittle patients. There was a significant correlation between age of onset of brittleness and age at menarche, with brittleness starting in most patients 2–5 yr after a normal-age menarche. This may implicate the hormonal and/or psychological changes at this time. Most type A brittle patients had secondary amenorrhea or oligomenorrhea at the time of study. Type B patients were older (32 and 38 yr) with long duration of diabetes (24 and 28 yr) and brittleness (20 and 28 yr). They were receiving a normal subcutaneous insulin dose (0.5 and 0.8 U/kg) and had a regular menses. Furthermore, brittleness appeared before menarche in these patients.

Effective Treatment of Insulin-Induced Edema Using Ephedrine

Objective— To control insulin-induced edema in a patient with poorly controlled IDDM. Research Design and Methods— A 31-yr-old woman with a 14-yr history of poorly controlled IDDM first developed peripheral edema 3 yr after diagnosis of IDDM; the edema worsened whenever insulin dosage was increased. In August 1991, severe edema developed after treatment of ketoacidosis, with body weight increasing from 46 to 61 kg. No evidence of cardiac dysfunction or autonomic neuropathy existed, and serum albumin was consistently normal. Results— Treatment with 15 mg of ephedrine every 8 h produced a prompt diuresis, with body weight falling by 4 kg in 48 h and by 12 kg within 1 wk. Conclusions— Ephedrine may be an effective treatment for insulin-induced edema and may be preferable to the use of diuretics in such patients.

Variability in vibration perception threshold among sites: a potential source of error in biothesiometry

Vibration perception threshold was measured with a biothesiometer by a single observer at both medial malleoli and both big toes in 110 diabetic patients aged 15-65 selected at random and in 64 non-diabetic subjects aged 20-65. The vibration perception threshold showed appreciable individual variation both between contralateral sites and between ipsilateral sites, differing by at least 30% between the big toes in 26 (24%) of the diabetic patients and 16 (25%) of the non-diabetic group. Variability between sites was significantly greater in the diabetics than the normal subjects. The vibration perception threshold exceeded published normal values at one or more sites in 22 of the diabetic patients but at all four sites in only four. The wide variability in vibration perception threshold among sites may be due to the tissue characteristics locally and, in diabetic patients, possibly to asymmetric neuropathy. Biothesiometer readings at single or unilateral sites may be unrepresentative or misleading.