G. Williams

GLUCAGON-LIKE PEPTIDE-1 7-36: A PHYSIOLOGICAL INCRETIN IN MAN

The physiological role of glucagon-like peptide-1 7-36 amide (GLP-1 7-36) in man was investigated. GLP-1 7-36-like immunoreactivity was found in the human bowel; its circulating level rose after oral glucose and after a test breakfast. When it was infused into seven volunteers at a rate to mimic its postprandial plasma concentration in the fasting state, plasma insulin levels rose significantly and glucose and glucagon concentrations fell. During an intravenous glucose load, it greatly enhanced insulin release and significantly reduced peak plasma glucose concentrations, compared with a control saline infusion, even inducing postinfusion reactive hypoglycaemia. By comparison, infusion of glucose-dependent insulinotropic peptide (GIP) to physiological levels was less effective in stimulating insulin release. These observations suggest that GLP-1 7-36 is a physiological incretin and that it is more powerful than GIP. The observation of greatly increased postprandial plasma GLP-1 7-36 levels in patients with postgastrectomy dumping syndrome suggests that it may mediate the hyperinsulinaemia and reactive hypoglycaemia of this disorder.

Characterization of glucagon-like peptide-1-(7-36)amide in the hypothalamus.

The distribution of glucagon-like peptide-1-(7-36)amide like immunoreactivity (GLP-1-(7-36)NH2 IR) in rat brain was determined. Highest concentrations were found in the hypothalamus. A combination of gel chromatography and anion exchange chromatography showed that the majority of hypothalamic immunoreactivity exactly corresponded in position to synthetic GLP-1-(7-36)NH2. Chromatographic analyses of rat ileum demonstrated a similar pattern, whereas in rat pancreas mainly a large proglucagon fragment and GLP-1 were indicated. Determination of the subcellular distribution by differential centrifugation of hypothalamic tissue revealed that most of the GLP-1-(7-36)NH2 IR was present in the synaptosome fraction. GLP-1-(7-36)NH2 was released from hypothalamic tissue slices in a calcium-dependent fashion by potassium-induced depolarization. Thus GLP-1-(7-36)NH2 appears to fulfil two criteria for a neurotransmitter. No change was found in its hypothalamic content in streptozocin-induced diabetic rats compared to normal controls but a decrease was seen in hyperinsulinemic hyperglycemic KKAy mice compared to KK mice.

Analgesic effect of somatostatin analogue (octreotide) in headache associated with pituitary tumours.

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Isolation and characterisation of GLP‐1 7–36 amide from rat intestine Elevated levels in diabetic rats

Glucagon‐like peptide‐1 (GLP‐1) was purified to homogeneity by HPLC and anion‐exchange chromatography. A molecular mass of 3297.4 Da was obtained by FAB mass spectrometry which corresponded exactly to GLP‐1 7–36 NH2, providing evidence that amidation occurs at an arginine residue during the post‐translational processing of GLP‐1. The distribution of GLP‐1 7–36 NH2‐like immunoreactivity (GLP‐1 7–36 NH2 IR) was determined in the rat gastrointestinal tract. Highest concentrations were found in terminal ileum and colon. Streptozocin‐induced diabetic rats, who showed a significant increase in food intake, had a significant increase of GLP‐1 7–36 NH2 IR in the colon.

REDUCED HYPOTHALAMIC NEUROTENSIN CONCENTRATIONS IN THE GENETICALLY-OBESE DIABETIC (OB/OB) MOUSE - POSSIBLE RELATIONSHIP TO OBESITY

Hypothalamic tissue levels of nine regulatory peptides (bombesin, calcitonin gene-related peptide [CGRP], galanin, neuromedin B, neuropeptide Y [NPY], neurotensin, somatostatin, substance P, and vasoactive intestinal peptide [VIP]) were compared in Aston obese diabetic (ob/ob) and lean (+/?) mice aged 4, 16, and 28 weeks. Neurotensin concentrations were significantly lower in ob/ob mice than in lean mice, with a 20% reduction (P = .03) in the whole hypothalamus at 4 weeks of age, a 24% reduction (P = .009) in the lateral hypothalamus at 16 weeks, and a 50% reduction (P = .0007) in the central hypothalamus at 28 weeks of age. Apart from a 42% increase in vasoactive intestinal peptide concentrations in the central hypothalamus of ob/ob mice at 28 weeks (P = .02), levels of the other eight peptides examined did not differ significantly between obese and lean groups. Neurotensin is known to cause anorexia and increased energy expenditure when injected into the central hypothalamus. Reduced hypothalamic neurotensin concentrations may reflect reduced neurotensinergic activity, which might contribute to hyperphagia and decreased energy expenditure, two major defects that contribute to obesity and diabetes in the ob/ob syndrome.

EFFECTIVE AND LASTING GROWTH-HORMONE SUPPRESSION IN ACTIVE ACROMEGALY WITH ORAL ADMINISTRATION OF SOMATOSTATIN ANALOGUE SMS 201-995

Oral administration of the long-acting somatostatin analogue, SMS 201-995 (Sandoz), was assessed in five patients with active acromegaly, four of whom had not responded to pituitary irradiation. Doses of 4-8 mg three times daily lowered mean 24 h growth-hormone concentrations by over 50% in every case, with suppression to below 10 mU/l for several hours after the morning dose. Despite effective suppression of serum insulin levels, deterioration in glucose tolerance was very slight, and the drug had no side-effects. Orally administered SMS 201-995 avoids the need for multiple daily injections and is potentially valuable in the medical treatment of acromegaly.

Increased Hypothalamic Neuropeptide Y Messenger RNA Levels in Two Rat Models of Diabetes

Elevated levels of immunoreactive hypothalamic neuropeptide Y have recently been reported both in streptozotocin‐induced diabetic rats and in the spontaneously diabetic BB rat. We have measured the levels of neuropeptide Y encoding messenger ribonucleic acid (mRNA) in both of these rat models to determine whether an increase in neuropeptide Y gene expression is a contributory factor to the increases in hypothalamic neuropeptide Y immunoreactive peptide content. In the hypothalami of both the spontaneously diabetic BB/E and the streptozotocin‐diabetic animals, neuropeptide Y mRNA showed significant elevations (to 204 ± 13% (± SE) and 387 ± 48% of control values, respectively, p < 0.01 for both). Our results demonstrate that two models of insulin‐deficient diabetes in the rat are associated with increased hypothalamic neuropeptide Y mRNA. Taken with the known effects of neuropeptide Y on food intake these results suggest that increased neuropeptide Y synthesis in the hypothalamus may be related to the hyperphagia seen in the diabetic condition.

Elevated neuropeptide Y concentrations in the central hypothalamus of the spontaneously diabetic BB/E Wistar rat

Insulin‐deficient diabetes causes hypothalamic and pituitary dysfunction. The possible role of hypothalamic regulatory peptides in mediating these disturbances was investigated in spontaneously diabetic BB/E Wistar rats. Concentrations of 10 regulatory peptides were measured in the central (nucleus‐rich) and lateral parts of the hypothalamus in 18 diabetic and 5 non‐diabetic BB/E rats. Diabetic rats were treated with either intensified or low‐dose insulin schedules to achieve moderate or severe hyperglycaemia (mean blood glucose concentrations, 8 and 20 mmol I−1 respectively). Neuropeptide Y concentration and content in the central hypothalamus were increased by 30–40% in both moderately and severely hyperglycaemic diabetic groups (p < 0.01). Lateral hypothalamic neuropeptide Y levels did not differ significantly between the groups. The only other peptide to show any significant difference between diabetic and control rats was calcitonin gene‐related peptide, whose central hypothalamic concentrations were significantly increased in the severely hyperglycaemic animals. Alterations of hypothalamic neuropeptide Y, which has potent experimental effects on hypothalamo‐pituitary function, may contribute to certain neuroendocrine disturbances in insulin‐deficient diabetes.

Treatment of Gut-Associated Neuroendocrine Tumors with the Long-Acting Somatostatin Analog, SMS 201-995

Neuroendocrine tumors associated with the gut are very rare (affecting only about 1/100,000 of the population), but are of exceptional interest from two major points of view.