Diabetologia

Clarke, B.; Ewing, D.; Campbell, I.

doi: 10.1007/BF01235856pmid: 387501

125 17 17 4 4 B. F. Clarke D. J. Ewing I. W. Campbell Diabetic and Dietetic Department and University Department of Medicine The Royal Infirmary Edinburgh Scotland Summary This review attempts to outline the present understanding of diabetic autonomic neuropathy. The clinical features have been increasingly recognised but knowledge of the localization and morphology of the lesions and their pathogenesis remains fragmentary. A metabolic causation as postulated in somatic nerves accords best with clinical observations. Most bodily systems, particularly the cardiovascular, gastrointestinal and urogenital, are involved with added disturbances of thermoregulatory function and pupillary reflexes. Possible effects on neuroendocrine and peptidergic secretion and respiratory control await definition. Current interest centres around the development of a new generation of tests of autonomic nerve function that are simple, non-invasive, reproducible and allow precision in diagnosis and accurate quantitation. Most are based on cardiovascular reflexes and abnormality in them is assumed to reflect autonomic damage elsewhere. Probably no single test suffices and a battery of tests reflecting both parasympathetic and sympathetic function is preferable. Little is known of the natural history. The prevalence may be greater than previously suspected and although symptoms are mild in the majority, a few develop florid features. The relation of control and duration of diabetes to the onset and progression of autonomic neuropathy is not clearly established. Once tests of autonomic function become abnormal they usually remain abnormal. Symptomatic autonomic neuropathy carries a greatly increased mortality rate possibly due to indirect mechanisms such as renal failure and direct mechanisms such as cardio-respiratory arrest. Improved treatment of some of the more disabling symptoms has been possible in recent years.

Dunn, P.; Cole, R.; Soeldner, J.; Gleason, R.; Kwa, E.; Firoozabadi, H.; Younger, D.; Graham, C.

doi: 10.1007/BF01235857pmid: 499681

125 17 17 4 4 P. J. Dunn R. A. Cole J. S. Soeldner R. E. Gleason E. Kwa H. Firoozabadi D. Younger C. A. Graham E. P. Joslin Research Laboratory and Joslin Clinic Division of the Joslin Diabetes Foundation, Inc. Boston MA USA New England Deaconess Hospital USA Department of Medicine Peter Bent Brigham Hospital and Harvard Medical School Boston MA USA Summary To examine the temporal relationship between Hb A Ic values and various indices of blood glucose control, 38 diabetic and 28 nondiabetic youth counsellors employed at two summer camps for diabetic children took part in an eight-week study. Each week fasting determinations were made of Hb A I , Hb A Ic , serum cholesterol, triglyceride and growth hormone and plasma glucose. Total daily urine glucose excretion was measured approximately two times per week, capillary glucose values were measured fasting and at 11 a. m. and 3 p. m. on two days per week, and urine glucose was measured semi-quantitatively four times per day. As Hb A I was correlated highly with Hb A Ic (r = 0.997), it was used as the primary index of glycosylated haemoglobin. The mean values of Hb A I , serum cholesterol and triglycerides and fasting plasma glucose were all significantly elevated in the diabetic group but only Hb A I values provided total separation of the two groups. Within the diabetic group the Week 8 Hb A I values showed a significant correlation with the Week 8 mean capillary glucose concentrations, the proportion of urine tests showing 2% and 0% glycosuria, and mean serum triglycerides. Correlations of Week 8 Hb A I with the mean values of these glycaemic parameters for each week of the study demonstrated low order correlations with the glycaemic measures of Week 1, and a progressive increase in the degree of correlation reaching a plateau with the glycaemic measures of Week 4 to 8. Similar correlation analysis using the Hb A I values from Week 4 confirmed these findings. Therefore, while Hb A I provides an index of the control of diabetes, it appears to be more acutely responsive to blood glucose alteration than generally recognized.

Waldhäusl, W.; Bratusch-Marrain, P.; Gasic, S.; Korn, A.; Nowotny, P.

doi: 10.1007/BF01235858pmid: 499682

125 17 17 4 4 W. Waldhäusl P. Bratusch-Marrain S. Gasic A. Korn P. Nowotny Abteilung für klinische Endokrinologie und Diabetes Mellitus Medizinische Universitätsklinik Austria Summary Insulin production rate has been estimated in healthy male volunteers (n = 16), and evaluated with respect to splanchnic glucose exchange. Insulin production rate was calculated from splanchnic immunoreactive C-peptide output. C-peptide secretion was estimated by the hepatic venous catheter technique both in the basal state and for 2h following ingestion of various glucose loads (0, 12.5, 25, 50, 75, and 100 g). The results demonstrate a basal insulin production rate of 0.017±0.002 U/min (mean±SEM) or 2.04 U/2 h. Values rose in a dose dependent manner from 2.6±1.1 U/2 h after ingestion of 12.5 g of glucose to 10.8±1.1 U/2 h following a glucose load of 100 g. Insulin retention by the liver was estimated at 0.012±0.001 U/min in the basal state, and ranged from 47–85% (70±2%) of production following an oral glucose load. It was also demonstrated 1) that the relative splanchnic glucose output was inversely related to the amount of ingested glucose, and reached a minimum when glucose in excess of 50 g was ingested; and 2) that hepatic glucose retention was directly proportional to insulin production rate (r=0.83; p<0.001; n= 15). It is suggested that the adaptive capacity of the splanchnic bed to retain glucose depending on the amount of ingested glucose guarantees that splanchnic glucose output fluctuates in healthy man only within a narrow range.

Rainbow, S.; Woodhead, J.; Yue, D.; Luzio, S.; Hales, C.

doi: 10.1007/BF01235859pmid: 91538

125 17 17 4 4 S. J. Rainbow J. S. Woodhead D. K. Yue S. D. Luzio C. N. Hales Department of Medical Biochemistry Welsh National School of Medicine Cardiff Wales Department of Clinical Biochemistry University of Cambridge, Addenbrooke's Hospital Cambridge England Department of Medicine The University of Sydney 2006 Sydney N.S.W. Australia Summary An indirect two-site immunoradiometric assay is described for the measurement of human proinsulin in plasma. Polyethylene tubes coated with purified guinea-pig antibodies to insulin were used to extract proinsulin and insulin from plasma. Rabbit antibody to human C peptide was then added to react with the C-peptide moiety of the bound proinsulin. The uptake of this antibody was measured by the subsequent binding of 125 I-sheep antibody to rabbit IgG. The binding of radioactivity to the tubes was a function of the proinsulin concentration in the sample. The sensitivity of the assay was 0.006 pmol/ml. Only 200 μl of plasma was required in the assay and the 125 I-labelled antibody was produced from readily available reagents. The polyethylene tubes remained stable for at least 5 months after coating. The mean fasting proinsulin level was 0.009 pmol/ml in sixteen normal subjects and 0.025 pmol/ml in twelve maturity onset diabetics. Oral glucose produced an 8 fold increase in proinsulin concentration but a decline in the plasma proinsulin/insulin molar ratio. Four patients with insulinoma had extremely elevated proinsulin levels and proinsulin/insulin ratios.

Yue, D.; Gibby, O.; Luzio, S.; Yanaihara, N.; Hales, C.

doi: 10.1007/BF01235860pmid: 91539

125 17 17 4 4 D. K. Yue O. M. Gibby S. D. Luzio N. Yanaihara C. N. Hales Department of Clinical Biochemistry University of Cambridge, Addenbrooke's Hospital Cambridge England Department of Bio-organic Biochemistry Shizuoka College of Pharmacy Shizuoka-Shi Japan Department of Medicine The University of Sydney 2006 Sydney N. S. W. Australia Summary An indirect two-site immunoradiometric assay for rat and mouse proinsulin using a rabbit antibody to synthetic rat C-peptide has been developed. The sensitivity of the assay is 0.006 pmol/ml. Proinsulin was 4.95% of the total proinsulin and insulin in extracts of rat pancreas and 5.45% in extracts of isolated rat islets. The mean fasting rat insulin and proinsulin concentrations were 0.13±0.09 pmol/ml (n=5) and 0.008±0.002 pmol/ml (n=5) respectively. The mean fasting mouse proinsulin concentration was 0.019±0.006 pmol/ml (n=8). In rats intravenous glucose produced a biphasic insulin response but proinsulin rose progressively to 0.021±0.011 pmol/ml at 45 min. In mouse oral glucose increased the proinsulin concentration to 0.13 pmol/ ml at 30 min. Proinsulin release from isolated rat islets was studied during intermittent or continuous high glucose (20 mmol/l) stimulation in static incubation. Significant increases in proinsulin release were only observed 90 min after initial exposure to high glucose whether glucose stimulation was continuous or intermittent. Both in vivo and in vitro glucose stimulation led initially to a fall in the proinsulin/ insulin molar ratio but later upon prolonged stimulation this progessively increased to above the basal value.

Rasch, R.

doi: 10.1007/BF01235861pmid: 499683

125 17 17 4 4 R. Rasch Second University Clinic of Internal Medicine, University Institute of Pathology Aarhus Kommunehospital Denmark Department of Cell Biology, Institute of Anatomy University of Aarhus Aarhus Denmark Summary A quantitative morphological study of the mesangial regions has been performed on the kidneys of two groups of insulin treated diabetic rats 6 months after the induction of diabetes. In one group reasonably good control of plasma glucose levels (182±20 (SD) mg/l00ml at 0800 h; 95±35 mg/100 ml at 2300 h) was achieved. This group showed no mesangial changes when compared to a non-diabetic control group. In the second diabetic group poor control was intended (plasma glucose 452±41mg/100 ml and 555±86mg/100 ml respectively). The following differences were noted when this group was compared to the non-diabetic controls and to the rats in which the blood glucose was well-controlled: 1. Increase in total mesangial volume per glomerulus by 42% and 38% (2p = 0.025 and 0.037); 2. Increase in the total amount of basement membrane-like material (BMLM) per glomerulus by 30 and 27% (2p = 0.030 and 0.046); 3. Increase in the total mesangial cell volume per glomerulus by 46 and 43% (2p = 0.033 and 0.048); 4. Increase in volume of electron dense material in the BMLM by about 200% compared to both groups (2p = 0.001 and 0.0003). The study has shown that the mesangial regions also are involved in the diabetic glomerulopathy of experimental diabetes. The morphological changes including increased amounts of basement membrane material are prevented by proper glycaemic control.

Feldman, J.; Reintgen, D.; Seigler, H.

doi: 10.1007/BF01235862pmid: 227764

125 17 17 4 4 J. M. Feldman D. S. Reintgen H. F. Seigler Durham Veterans Administration Medical Center and Departments of Medicine and Surgery Duke University Medical Center Durham North Carolina USA Summary Hamster and rat insulinomas were assayed for norepinephrine, dopamine and serotonin concentration and for monoamine oxidase and catechol-o-ethyltransferase (COMT) activity. The concentration of norepinephrine (mean 0.55 μmol/kg, range <0.20 to 2.64 μmol/kg) and serotonin (mean 5.22 μmol/kg, range <0.6 to 26.5 μmol/kg) in hamster insulinomas were comparable to previously reported concentrations. Dopamine concentration (mean 0.34 μmol/kg, range <0.20 to 0.95 μmol/kg) was only 2 to 2.5% of that reported previously. Monoamine oxidase activity of the hamster and rat insulinomas were comparable to those of normal hamster islets. In contrast, the COMT activity of both insulinomas was much greater than the COMT activity of normal pancreatic islets of both species and was greater than in several other tissues and tumours. The tumour COMT, which was predominantly in the cytosol, was Mg 2+ dependent and had a comparable sensitivity to inhibition by tropolone as purified beef-liver COMT. Hamster insulinoma monoamine oxidase was more sensitive than rat insulinoma monoamine oxidase to inhibition by tranylcypromine and deprenyl, while rat insulinoma monoamine oxidase was more sensitive to inhibition by clorgyline and was more heat labile.

Dolais-Kitabgi, J.; Marchand-Brustel, Y.; Freychet, P.

doi: 10.1007/BF01235863pmid: 387502

125 17 17 4 4 J. Dolais-Kitabgi Y. Le Marchand-Brustel P. Freychet Institut National de la Santé et de la Recherche Médicale (I. N. S. E. R. M.), Groupe U 145, Department of Experimental Medicine University of Nice France Summary The pancreatic content of somatostatin, insulin, and glucagon and the hypothalamic content of somatostatin were examined in ob/ob mice at various ages and in goldthioglucose-obese mice. The total pancreatic content of somatostatin was increased in ob/ob mice compared to controls: 92 ng vs 75 ng (a 22% increase) at 2 months of age; 208 ng vs 131 ng (a 60% increase) at 6 months of age; and 184 ng vs 118 ng (a 60% increase) at 8 months of age. The total pancreatic content of glucagon in ob/ ob mice was already enhanced by 70% over controls at 2 months of age (301 ng vs 173 ng) and did not increase further at later stages, whereas that of insulin progressively rose with age. In goldthioglucoseobese mice the pancreatic content of insulin was also increased but to a lesser extent than in ob/ob mice; the pancreatic levels of somatostatin and glucagon were unaltered. In both ob/ob mice (regardless of age) and goldthioglucose-obese mice, there was no significant change in the hypothalamic content of somatostatin compared with that of lean controls.

Köbberling, J.; Creutzfeldt, W.

doi: 10.1007/BF01235864pmid: 499684