Keith D. Buchanan

Normalization of Insulin Responses to Glucose by Overnight Infusion of Glucagon-Like Peptide 1 (7–36) Amide in Patients With NIDDM

Glucagon-like peptide 1 (GLP-1) is a natural enteric incretin hormone, which is a potent insulin secretogogue in vitro and in vivo in humans. Its effects on overnight glucose concentrations and the specific phases of insulin response to glucose and nonglucose secretogogues in subjects with NIDDM are not known. We compared the effects of overnight intravenous infusion of GLP-1 (7-36) amide with saline infusion, on overnight plasma concentrations of glucose, insulin, and glucagon in eight subjects with NIDDM. The effects on basal (fasting) β-cell function and insulin sensitivity were assessed using homeostasis model assessment (HOMA) and compared with seven age- and weight-matched nondiabetic control subjects. The GLP-1 infusion was continued, and the first- and second-phase insulin responses to a 2-h 13 mmol/l hyperglycemic clamp and the insulin response to a subsequent bolus of the nonglucose secretogogue, arginine, were measured. These were compared with similar measurements recorded after the overnight saline infusion and in the control subjects who were not receiving GLP-1. The effects on stimulated β-cell function of lowering plasma glucose per se were assessed by a separate overnight infusion of soluble insulin, the rate of which was adjusted to mimic the blood glucose profile achieved with GLP-1. Infusion of GLP-1 resulted in significant lowering of overnight plasma glucose concentrations compared with saline, with mean postabsorptive glucose concentrations (2400–0800) of 5.6 ± 0.8 and 7.8 ± 1.4 mmol/l, respectively (P < 0.0002). Basal β-cell function assessed by HOMA was improved from geometric mean (1 SD range), 45% β (24–85) to 91% β (55–151) by GLP-1 (P < 0.0004). First-phase incremental insulin response to glucose was improved by GLP-1 from 8 pmol/l (-–33) to 116 pmol/l (12–438) (P < 0.005), second-phase insulin response to glucose from 136 pmol/l (53–352) to 1,156 pmol/l (357–3,748) (P < 0.0002), and incremental insulin response to arginine from 443 pmol/l (172–1,144) to 811 pmol/l (272–2,417) (P < 0.002). All responses on GLP-1 were not significantly different from nondiabetic control subjects. Reduction of overnight glucose by exogenous insulin did not improve any of the phases of stimulated β-cell function. Prolonged intravenous infusion of GLP-1 thus significantly lowered overnight glucose concentrations in subjects with NIDDM and improved both basal and stimulated β-cell function to nondiabetic levels. It may prove to be a useful agent in the reduction of hyperglycemia in NIDDM.

Neuroendocrine tumors: A European view

A center in Belfast, Northern Ireland, has established a register for tumors of the gastroenteropancreatic endocrine system. Carcinoid tumors occur most frequently. Of the non-carcinoid tumors, insulinomas, gastrinomas, and unknown types have the highest incidence, with other types being extremely rare. The potentially remediable nature of the tumors is stressed, and frequently a good quality of life can be experienced even in the presence of metastatic disease. The syndromes are probably underdiagnosed as they present with clinical features for which there are more common explanations, and appropriate diagnostic methods are therefore not used. The management of the syndromes is reviewed with particular emphasis on the treatment of patients with inoperable disease. Histamine (H2)-receptor antagonist therapy has made an impact in Zollinger-Ellison syndrome, and streptozotocin and somatostatin analogues can control tumor growth and endocrine syndromes, respectively.

Serum neurone specific enolase (NSE) levels as an indicator of neuronal damage in patients with cerebral infarction

Abstract. A radioimmunoassay has been developed and used to measure serum neurone specific enolase (NSE) concentrations in 24 patients, following cerebral infarction. A significant correlation between cerebral infarct volume and maximum serum NSE concentration was observed (P= 0·047). Serum NSE was also assayed at times 24, 48, 72 and 96 h post ictus. At 72 h a significant correlation existed between serum NSE levels and infarct volume (P= 0·012), and levels appeared to be approaching statistical significance at 48 h (P=0·067). No correlation existed at 24 and 96 h. In addition serum concentrations of NSE were compared to clinical outcome as determined by the Glasgow Outcome Score. Using the Mann‐Whitney U test, there was no significant difference in maximum NSE level between patients graded 1–3 on the Glasgow Outcome Score and those graded 4 and 5. However, further studies are required on a larger population to more completely assess this. NSE may prove to be a useful marker of neuronal damage in the study of stroke, with particular application in the assessment of treatment.

Familial nesidioblastosis as the predominant manifestation of multiple endocrine adenomatosis

Abstract The incidence of endocrine abnormalities in eight members of a family with multiple endocrine adenomatosis was compared with that in five nonrelated subjects with islet cell tumors and in seven normal control subjects. Three members of the family had documented islet cell hyperplasia, adenoma and/or carcinoma associated with hypoglycemia or the Zollinger-Ellison syndrome, and all but one member of the family was found to have hypersecretion of insulin, often associated with elevated blood glucagon and/or gastrin levels. Five members had hyper-insulinism but were asymptomatic, although several demonstrated glucose intolerance. Asymptomatic hypercalcemia and abnormal adrenal function were noted in some subjects. There was no evidence of primary abnormalities in pituitary function or of catecholamine and 5-hydroxyindoleacetic acid levels in the family subjects. The nonfamily subjects with insulinoma had no other endocrine abnormalities. In one nonfamily subject, who may also have multiple endocrine adenomatosis, the Zollinger-Ellison syndrome was associated with high blood gastrin and insulin levels with glucose intolerance. It is proposed that the basic genetic defect in the family with multiple endocrine adenomatosis involves hyperplasia of the primordial cell of the islets of Langerhans (nesidioblastosis) with chronic oversecretion of one or more islet cell hormones. Secondary changes in other endocrine glands may then evolve as a consequence of the islet cell hormone excess(es). A high incidence of asymptomatic endocrine abnormalities was found in this and other studies. It is suggested that when abnormal growth or function of one endocrine gland is detected, a careful search for asymptomatic involvement of other glands should be made in the patient and his immediate relatives.

Serum neurone‐specific enolase as an indicator of stroke volume

Serum neurone‐specific enolase (NSE) and computerized tomography (CT) stroke volume were compared in patients admitted within 24 h of an acute stroke. Serum samples were obtained on admission and daily for the next 4 days. Of 163 patients, CT scans revealed 25 with intracerebral haemorrhages, one haemorrhagic infarct and 83 measurable acute infarcts. The serum NSE levels of those with infarcts was significantly higher than in those with haemorrhages at 48 (P = 0.0003) and 72 h (P = 0.04). The maximum serum NSE value tended to occur later in those with large infarcts (P = 0.0035). There was a significant correlation between infarct volume and serum NSE at 48 h (r = 0.27, P = 0.015) and 96 h (r = 0.27, P = 0.015) and with the maximum serum NSE over the 4 days (r = 0.36, P = 0.001). There was no significant correlation between haemorrhage volume and NSE. In conclusion, serum NSE may be a useful marker of infarct volume in studies of therapy in acute stroke. Sampling for NSE should continue, at least in those with large infarcts, for longer than 4 days. Serum NSE cannot be used to distinguish between haemorrhage and infarction in patients with an acute stroke.

Appendiceal goblet cell carcinoids: a clinicopathological and immunohistochemical study

Goblet cell carcinoids are uncommon but distinctive tumours of the appendix. We have reviewed 11 cases diagnosed within the period 1976‐1990. The mean age at presentation was 58 years (range 24–76), with a female: male ratio of 8:3. At presentation, in seven patients tumour was confined to the appendix or mesoappendix (mean age 51) and in four there was extension beyond the appendix (mean age 69). Of the seven patients with localized tumour, six are alive and without clinical disease after a mean follow‐up period of 32 months and one died with recurrent tumour after 10 years. Of the four with more extensive disease, two died during follow‐up (at 23 months with probable liver metastases and at 16 months with intestinal obstruction) and two are alive, one with disease and one clinically disease‐free. Immunohistochemistry showed that all of the tumours stained positively for either neuron‐specific enolase, chromogranin A or protein gene product 9.5. No tumour stained with antiserum to serotonin or substance P and none showed glucagon‐like immunoreactivity, but four cases stained positively for pancreatic polypeptide, an unusual feature in midgut carcinoids.

Glucose tolerance, plasma insulin, HDL cholesterol and obesity: 12-year follow-up and development of coronary heart disease in Edinburgh men

The insulin response to a standard oral glucose tolerance test (OGTT) and other anthropometric and biochemical risk factors for coronary heart disease (CHD) were measured in a random sample of 107 Edinburgh men, who were initially studied in 1976 when they were 40 and who were reexamined in 1988-89. Fasting glucose and glucose response to OGTT were higher in 1988-89 than in 1976. In contrast, insulin levels did not differ between the initial and follow-up study either before or after the glucose load. Body mass indices increased, except triceps skinfold. Changing patterns in both fasting and OGTT insulin or glucose levels in individuals were related to changes in bodyweight or in subscapular skinfolds. Modifications in serum total and HDL cholesterol were related to changes in fasting insulin and insulin area, respectively, but not to glucose data. Eleven men developed clinical CHD. Neither glucose nor insulin measures obtained in 1976 differed between those with and without CHD. Weight-height index and abdominal skin-folds were higher in those with CHD. HDL cholesterol was significantly lower (P less than 0.05). Abdominal skin-fold but not body mass index remained significant when adjusted for HDL cholesterol. This small study confirms the importance of central obesity and low HDL cholesterol but failed to identify insulin as a risk factor for CHD in this Scottish population.

Immunocytochemical demonstration of 5-hydroxytryptamine (serotonin) and vertebrate neuropeptides in the nervous system of excysted cysticercoid larvae of the rat tapeworm, Hymenolepis diminuta (Cestoda, Cyclophyllidea)

The localisation and distribution of 5-hydroxytryptamine (5-HT, or serotonin) and a number of vertebrate neuropeptides in the nervous system of excysted (0–24 h) cysticercoid larvae of Hymenolepis diminuta were determined by an indirect immunofluorescence technique in wholemount preparations. In the central nervous system, cell bodies and nerve fibres immunoreactive to 5-HT are present in the main commissure, lateral and rostellar ganglia, and the longitudinal nerve cords and their connectives. In the peripheral nervous system, immunoreactive nerve fibres occur in a poorly developed nerve plexus within each sucker. Among the vertebrate peptides tested, antisera to pancreatic polypeptide (PP), polypeptide YY (PYY), peptide histidine isoleucine (PHI) and gastrin-releasing peptide (GRP) gave positive results. Immunoreactivity to PP and PYY paralleled that of 5-HT, with greater numbers of cell bodies present in the different locations within the scolex nervous system, and the sucker plexus being more prominent. The number of PP-reactive cells in the lateral ganglia and main lateral, longitudinal nerve cords increased over the 24-h period in culture. Results with antisera of different specificities to PP and PYY suggest that the immunoreactivity may be due to a peptide with closer structural affinity to PYY than to PP. Immunoreactivity to PHI is restricted to the main lateral nerve cords in the body of 0-h worms, extending into the median nerve cords by 12 h and 24 h. Immunoreactivity to GRP became evident after 12 h in culture and was confined to the longitudinal nerve cords, in particular the median nerve cords. The results are discussed in relation to the proposed transmitter and regulatory roles of 5-hydroxytryptamine and the neuropeptides.

Neonatal secretion of gastrin and glucagon

Plasma gastrin and glucagon levels were estimated in mothers after labour, and in their babies at birth and on the fourth day of life. The newly born baby appears to secrete gastrin independently and the plasma levels are higher on the fourth day of life. The cord gastrin level is lower when labour is induced or augmented by the intravenous infusion of oxytocin. Our results do not exclude the possibility that gastrin is transferred from mother to baby during a spontaneous labour. Such a maternal component of cord gastrin may be responsible for neonatal gastric hyperacidity. The mean cord glucagon level is higher than the maternal level at birth and the fourth day level is higher than the cord level. The C-terminal reactive glucagon-like immunoreactivity (C-GLI) in the cord blood is lower when oxytocin has been used during labour. Maternal or placental transfer of C-GLI during labour to the spontaneously born baby is one possible explanation of this finding. The raised glucagon levels on the fourth day may explain why there is low gastric acidity at this time despite the gastrin level being higher than at birth. No relation could be deduced between the C-GLI, i.e. pancreatic glucagon level, and the blood glucose level either at birth or on the fourth day of life.

Isolation of glucagon-like immunoreactivity of gut by affinity chromatography on anti-glucagon antibodies coupled to sepharose 4B

Abstract 1. 1. Antibodies raised in rabbits against porcine pancreatic glucagon were coupled to Sepharose 4B. The resultant complex was used to purify porcine pancreatic glucagon and glucagon-like immunoreactivity of pig ileum. The purified glucagon-like immunoreactivity was eluted from gel-filtration columns at positions corresponding to proteins of mol. wt. 12 000 (large glucagon-like immunoreactivity) and 3500 (small glucagon-like immunoreactivity). The former fraction accounted for over 95% of the total immunoreactivity. 2. 2. Large glucagon-like immunoreactivity contained at least three N-terminal amino acids, glycine, alanine and methionine, and was separated into three immunoreactive components by electrophoresis. 3. 3. Large glucagon-like immunoreactivity did not display the biological activity of pancreatic glucagon.