Glucagon immunoreactivity and antidiabetic action of somatostatin in the totally duodeno-pancreatectomized and gastrectomized human.

Ten patients who had been totally duodeno-pancreatectomized and totally (N = 1) or partially gastrectomized (N = 9) for chronic pancreatitis (N = 9) or pancreatic carcinoma (N = 1) were investigated. None had a measurable basal level of either plasma C-peptide or a C-peptide response to i.v. glucagon. Immunoreactive glucagon (IRG) was present in all patients, and the mean level (69 +/- 8 pg/ml) was not significantly different from the mean observed in normal subjects (81 +/- 16 pg/ml). Plasma IRG was unequivocally stimulated by arginine in 2 of the 10 subjects. The effect of somatostatin on plasma glucose and IRG during an oral glucose tolerance test was studied in 5 of the 10 patients. The effects of somatostatin on spontaneous hyperglycemia, plasma growth hormone, and IRG after withdrawal of insulin treatment was studied in 4 patients. Somatostatin blunted both the hyperglycemic and paradoxical IRG responses to the glucose challenge, and reduced the spontaneous rise of blood glucose that occurred after insulin withdrawal. This latter effect was not related to clear-cut changes in plasma growth hormone or in IRG. These data confirm the existence of circulating IRG in pancreatectomized patients and demonstrate the presence of circulating IRG in a completely gastrectomized and pancreatectomized patient. The somatostatin-induced improvement in glucose tolerance in the oral glucose tolerance test seems to be related to a reduction of the paradoxical IRG response. In contrast, the inhibition by somatostatin of the rise in blood glucose which occurs after insulin withdrawal does not seem to be mediated through IRG or growth hormone.

Plasma beta-thromboglobulin response to insulin-induced hypoglycemia in type I diabetic patients.

The effect of an insulin-induced hypoglycemia was examined in 14 type I diabetic patients. After an overnight blood glucose normalization, each patient received an additional intravenous bolus of 3 U regular insulin at 0900 h (time 0). Blood glucose was continuously recorded up to 180 min. Plasma samples were assayed for beta-thromboglobulin (beta TG, ng/ml), pancreatic glucagon (pg/ml), cortisol (microgram/dl), and growth hormone (ng/ml) 30 min before the insulin stress, at time 0, at blood glucose nadir, and at 180 min. The blood glucose fell from a baseline level of 85.0 +/- 3.2 mg/dl to a nadir value of 39.2 +/- 1.9 mg/dl (P less than 0.001) reached at an average time of 41.4 +/- 4.9 min. Plasma beta TG increased significantly (P less than 0.05) during the insulin stress: 93.4 +/- 23.7 ng/ml at nadir versus 42.5 +/- 5.9 at time 0. Plasma cortisol and growth hormone were significantly increased (P less than 0.02 and P less than 0.01) at nadir compared with time 0 values. Plasma pancreatic glucagon was higher at nadir than at time 0, but the difference was not significant. The present results indicate that in vivo platelet activation can be triggered by hypoglycemic episodes in insulin-treated diabetic patients.

Stable insulin for implantable delivery systems: in vitro studies with different containers and solvents.

The stability of a new insulin formulation (lyophilized U100 insulin, Organon) was investigated in vitro in conditions reproducing those of in vivo implanted devices, i.e., constant horizontal agitation at 37 degrees C for 4 wk in various containers and 8 wk in different solvents. Physical stability was assessed by ultraviolet absorption, chemical stability by HPLC, and biological stability by hypoglycemia tests in mice. Insulin precipitated in glass vials but remained clear and active in polyethylene reservoirs and after passage through catheter and pumps in motion, although only 83-90% of insulin was delivered chemically intact. In acidic solvent, insulin showed a major gradual transformation into deamidized derivatives (up to 78% after 8 wk), although still fully active and clear, as expected from previously published excellent in vivo results with acidic insulins. Heparin addition to neutral insulin solution (500 IU/ml) did not alter the properties of the two compounds and might thus be tried to prevent in vivo catheter obstruction due to fibrin deposition.

Influence of indigestible fibers on glucose tolerance.

In eight patients exhibiting chemical diabetes mellitus with a poststimulative hypoglycemia, we observed that the pattern of the oral glucose tolerance test (OGTT) was improved when indigestible fiber was added to the oral glucose load. As compared with a standard OGTT, the peak blood glucose, expressed as per cent change from baseline, was particularly blunted by pectin or by cellulose phosphate but remained unchanged with cellulose supplementation. The time interval required to reach the blood glucose peak was significantly prolonged with pectin. The rate of blood glucose rise was reduced to a greater extent by pectin than by cellulose phosphate, which in turn was more efficient than cellulose. The blood glucose nadir expressed as per cent change from baseline was blunted by pectin, while the results were not significantly different after addition of either cellulose phosphate or cellulose. On the other hand, the plasma immunoreactive insulin did not show any significant change whether the glucose was given with or without one of the aforementioned types of fiber. From these results, it is concluded that an additional fiber intake may be of interest in the management of chemical diabetes. The use of pectin may diminish the poststimulative hypoglycemia.

Comparative analysis of soluble porcine and human insulin (Novo) using the artificial pancreas.

The porcine-extracted monocomponent insulins and human insulin (Novo) obtained by enzymatic conversion of porcine insulin had similar effects on glycemia balance when compared by means of an artificial pancreas during two 48-h studies 2 or 3 days apart. There was no significant difference between the maximum and minimum blood glucose circadian variations, the glycemic drops, and the Schlichtkrull coefficient. The speed of increase and decrease of glycemia during meals was slightly slower with human insulins than with porcine insulins, but the difference was not significant. Although comparable, the insulin requirements (per gram of ingested carbohydrate) were proportionately greater in the morning than during the rest of the day; the baseline requirements were also similar, but showed a trend toward increase during the day with both insulins.

Long-term ambulatory peritoneal insulin infusion of brittle diabetes with portable pumps: comparison with intravenous and subcutaneous routes.

This work compares different routes of insulin infusion via portable pumps with chronically implanted catheters and evaluates the long-term feasibility of the technique. Six severely unstable (i.e., uncontrolled by optimized intensive insulin therapy) diabetic individuals (age range: 35 +/- 4 yr; duration: 11 +/- 2 yr) were selected. Promedos pumps (Siemens A. G., Erlangen, West Germany) were exclusively used because of their portability and long-life insulin reservoir (1-mo duration with U40 acidic Hoechst insulin). Each patient underwent three randomized 1-mo periods of insulin infusion: subcutaneous (s.c.), intravenous (i.v.), and intraperitoneal (i.p.) before the catheter was left indefinitely in one of these sites. Diabetic control was improved and insulin doses reduced whatever the route of infusion, although the s.c. route gave slightly higher values. These results did not deteriorate with time: mean blood glucose was 126 +/- 3 mg/dl and HbA1 was 8.3 +/- 0.6% after 10-18 mo of constant infusion versus 237 +/- 35 mg/dl and 10.0 +/- 0.8%, respectively, under conventional therapy. From a practical point of view, the i.p. route seems preferable since all s.c. catheters provoked local reactions after less than 1 mo and the two chronic i.v. catheters obstructed after 8 and 9 mo. All other incidents were minor and curable without removal of the catheters. All patients argued improvement of both diabetes and quality of life and no one has resigned so far. Thus, the i.p. infusion technique seems beneficial to unstable diabetic individuals and adaptable to long-term therapy, although intensive education and careful follow-up are necessary.

Comparative study of NPH human insulin (recombinant DNA) and pork insulin in diabetic subjects: preliminary report.

Continuous blood glucose monitoring in six insulin-dependent diabetic patients shows that the biologic action of NPH human insulin (recombinant DNA) and pork insulin is similar. Nevertheless, the activity of NPH human insulin seems faster and more pronounced since minimal glycemia is lower and more rapidly reached after human insulin. The speed of glycemic increase is slightly lower and the decrease is faster with NPH human insulin; thus the area under the NPH human insulin-induced glycemic curve is less wide, but differences are not significant. Our data favor a faster and more potent effect of NPH human insulin.

Continuous peritoneal insulin infusion with portable pumps: factors affecting the operating life of the chronic catheter.

Fifty-nine chronic peritoneal catheters made of polyethylene covered with silastic were used to treat 43 IDDM patients peritoneally for 3-34 mo (mean 14 mo) with portable peristaltic pumps and U40 acidic insulin. The operative life of the catheters was determined by actuarial analysis. The mechanisms of catheter failure were determined by preremoval x-ray opacification, removal under laparoscopic examination, and electron microscopic analysis of the catheter. Factors such as age, sex, duration of diabetes, implantation and tunnelization procedures, length of the catheter, and rate of infusion were analyzed. The 50% survival rate of the catheters was 16 mo. Six catheters were irreversibly obstructed by intraluminal fibrin formation and/or extraluminal adhesions, although insulin precipitation was never encountered. Seven catheters had to be removed because of a persisting local infection. Other causes were negligible (misinsertion, irreparable break). The only factor significantly related to incidence of catheter failure was gender with respect to obstruction (1 obstruction among 24 women versus 5 among 19 men, P less than 0.03).

Factors involved in catheter obstruction during long-term peritoneal insulin infusion.

OBJECTIVE: To analyze the efficacy of ECPII and the factors responsible for technical problems often encountered. This treatment has been in use with IDDM patients since 1980. RESEARCH DESIGN AND METHODS: Forty-four IDDM patients were treated by ECPII for 42-78 mo (mean, 53 mo). RESULTS: Glycemic equilibrium was improved during treatment (mean plasma glucose level, 7.6 mM; mean GHb level, 8%). Catheter blockage was the main reason for ECPII failure (74%). Mean catheter survival of each catheter, determined by actuarial analysis, was 11.7 mo and significantly decreased with subsequent implantation. SEM of the catheter tips showed deposits composed of fibrin and cells occluding the inner lumen. Factors such as age, sex, local infection, and low insulin basal rate were not found to have any incidence on the catheter survival. Placement of the catheter in the upper part of the peritoneum, however, increased catheter survival. Anti-insulin antibodies did not seem to be directly involved in blockage. CONCLUSIONS: We conclude from this long-term experience that during ECPII, catheter blockage remains the major recurring complication, probably involving a local immune-inflammatory response in the peritoneum.

Tyrosine-kinase defect of the insulin receptor in cultured fibroblasts from patients with lipoatropic diabetes.

Postbinding defects in insulin action were described previously in cultured fibroblasts from six patients with lipoatropic diabetes. To define the contribution of the insulin receptor tyrosine kinase in these defects, we studied autophosphorylation and kinase activity of lectin purified receptors from these six patients and six normal cell lines. The patients' insulin receptors, prepared by precipitation with polyethylene glycol, had normal insulin binding characteristics and autophosphorylation properties, but a 56% decrease in the tyrosine kinase activity toward an exogenous substrate. To identify more subtle qualitative defects in autophosphorylation, insulin receptors were sequentially immunoprecipitated and analyzed for their phosphoaminoacid content. The phosphorylated receptors precipitated with an antiphosphotyrosine antibody contained labeled phosphotyrosine, whereas those in the supernatant, when further precipitated with an antireceptor antibody, contained only phosphoserine. Under these conditions, the insulin-stimulated autophosphorylation of tyrosine was significantly decreased by 54% in the patient receptors compared to normal subjects' receptors. In addition, insulin-like growth factor-I stimulation of autophosphorylation of its receptor was reduced by 59% in the patients' cells compared to those from normal subjects. We conclude that fibroblasts from patients with lipoatropic diabetes have defects in the tyrosine kinase activity of their insulin and their insulin-like growth factor-I receptors that might give rise to the in vitro hormone resistance and be related to the in vivo hormone resistance that occurs in these patients.

Evidence and mechanism for pectin-reduced intestinal inorganic iron absorption in idiopathic hemochromatosis.

The intestinal absorption of iron was measured in 13 patients suffering from idiopathic hemochromatosis by using a double radiotracer technique. For each patient, iron absorption was determined in the fasting state, i.e., under basal conditions, and after an oral indigestible fiber load (9 g/m2 of body surface) with either pectin (group I: eight patients) or cellulose (group II: five patients). The results were compared with those from a group of seven normal control subjects investigated under basal conditions. The patients with haemochromatosis (groups I and II) had a significant increase in the basal value of fractional iron absorption as compared with controls. In the patients of group I, the pectin induced a significant fall in fractional iron absorption (P less than 0.02). In group II, iron absorption rates remained unchanged whether or not cellulose was given. Furthermore, we found in vitro that pectin had a high iron binding activity, while cellulose bound none. From the present study, we conclude that pectin but not cellulose reduces iron absorption by forming unabsorbable complexes with dietary iron. Thus, enrichment of the diet with foods providing significant amounts of noncellulosic dietary fibers, such as pectin, may be useful in the management of hemochromatosis patients.

Effects of dietary fiber on postprandial glycemic profiles in diabetic patients submitted to continuous programmed insulin infusion.

Conventional (C) or fiber supplemented (F) test breakfast and lunch were given on 3 successive randomized days to six insulin-dependent diabetic patients treated with continuous programmed insulin infusion. Meal distribution was as follows: day 1 (C breakfast and C lunch), day 2 (F breakfast and C lunch), day 3 (F breakfast and F lunch). No rise in blood glucose (BG) was observed after F breakfast (days 2 and 3) while a small rise in BG occurred after the C breakfast (day 1). Significant differences were observed between day 1 and days 2 and 3 for absolute BG values as well as for BG changes (delta BG) from base-line. At lunch slight differences in delta BG were only noted at 45 min (p less than 0.05) between days 2 and 3, while there was no difference between days 1 and 2. Our results indicate that fiber supplementation is useful even in pump-treated insulin-dependent diabetics but that F breakfasts have no influence on the carbohydrate tolerance to the subsequent lunch.

Contrasting effects of captopril and nifedipine in normotensive patients with incipient diabetic nephropathy.

Microalbuminuria is a reliable predictor of the eventual development of overt diabetic nephropathy and blood pressure is known to accelerate the course of this nephropathy. In the present studies, the effect of a 6-week treatment by placebo (n = 7), nifedipine (n = 7) and captopril (n = 8) on renal function and urinary excretion of albumin (UAE) was investigated in normotensive, insulin-dependent, diabetic patients with incipient nephropathy (UAE greater than 15 micrograms/min). No change in arterial pressure, renal function or UAE was observed in the placebo group. In response to captopril and nifedipine, mean arterial pressure decreased slightly and similarly in both groups. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) increased to a similar extent in the nifedipine group, thus resulting in no change in filtration fraction (FF). In response to captopril, GFR was unchanged whilst ERPF increased; as a consequence FF decreased. Opposite changes in UAE were observed in response to the two treatments; UAE decreased by 40% in the captopril group and by 40% in nifedipine-treated patients. These results indicate that intrarenal changes may be crucial with respect to the effect of therapy on UAE. It is suggested that only agents which reduce FF and probably intraglomerular capillary pressure, such as converting enzyme inhibitors, alter UAE and may possibly interfere with the course of incipient diabetic nephropathy in normotensive patients.

Thyroid status and muscle protein breakdown as assessed by urinary 3-methylhistidine excretion: study in thyrotoxic patients before and after treatment.

Urinary 3-methylhistidine (3MH) excretion was studied in nine thyrotoxic patients before and after treatment. Urinary creatinine (Cr) output was also measured and was low in the thyrotoxic subjects before treatment. Thus, although urinary output of 3MH was not greater than among the control population when expressed per subject, it was significantly elevated when expressed as the ratio of 3MH to Cr; this ratio fell significantly, reaching normal control values after a euthyroid state was obtained. In one patient who became hypothyroid, the 3MH/Cr ratio fell under the control value. There was a significant linear correlation between the 3MH/Cr ratio and the hormonal variables (T3, T4, FT4l); moreover, variations in the 3MH/Cr ratio and variations in the T3 level were closely correlated. 3-Methylhistidine appears to be a reliable index of muscular breakdown in thyrotoxicosis. From our results, it can be concluded, first of all, that hyperthyroidism is accompanied by an increased muscular catabolism, and, second, that the return to a euthyroid state results in an immediate normalization of muscular breakdown.

Influence of the frequency of gonadotropin-releasing hormone (GnRH) administration on ovulatory responses in women with anovulation.

In attempt to optimize gonadotropin-releasing hormone (GnRH) treatment of anovulation, we compared the effect of intravenous GnRH administration at three pulse intervals (PI) during 63 cycles in 30 anovulatory patients who had: (1) amenorrhea secondary to anorexia nervosa (group I: 10 patients, 21 cycles); (2) unexplained anovulation with normal to high luteinizing hormone plasma levels (group II: 12 patients, 24 cycles); and (3) polycystic ovarian disease (PCOD) (group III: 8 patients, 18 cycles). Ovulation was achieved more frequently in group I (85%) than in group II (41%) or in group III (50%). In both groups I and II, the frequency of ovulatory responses was not different with the PI used, and 6 of the 17 women treated for infertility conceived; 3 with 90-minute PIs, 2 with 64-minute PIs, and 1 with 128-minute PIs. In women with PCOD, seven of the nine ovulatory responses and three pregnancies were obtained with 128-minute PIs. The overweight women with PCOD did not respond reliably to GnRH at the doses used, i.e., 4 to 15 micrograms per pulse. In all groups, the urinary estrone and estradiol preovulatory peak, duration of luteal phase, progesterone levels, and preovulatory follicle diameter were unrelated to the frequency of GnRH administration.

Secondary failure of oral antidiabetic and dietetic therapy in non-insulin-dependent diabetes mellitus. Remission through short sessions of continuous intravenous insulin infusion.

The infusion of periodic intravenous insulin for the equilibrium of the diabetic state is proposed for cases of non-insulin-dependent diabetes mellitus (NIDDM) that have become resistant to oral treatment. In order to re-establish the efficacy of oral antidiabetic treatment, 37 patients with NIDDM presenting secondary failure to diet and oral antidiabetic therapy were subjected to sessions of continuous intravenous insulin infusion, resulting in transitory normal blood sugars. With a diminution of symptoms, an increase in the efficacy of oral treatment was noted in 18 cases (48.6%), allowing the continuation of treatment without disturbance of the equilibrium over periods of 6 and 12 months. This improvement is not concurrent with the rise in glucagon-stimulated insulin secretion as evidenced by C-peptiduria and basal C-peptidemia. An improvement in insulin sensitivity (not investigated in this study) might explain this beneficial effect. Periodic intravenous infusions of insulin, based on the diabetic equilibrium, are proposed for the treatment of NIDDM patients that have become resistant to oral therapy.

Failure to achieve tight control of plasma cholesterol and apolipoprotein B with intraperitoneal insulin infusion in type 1 diabetes.

The best route of insulin administration by infusion pumps remains a subject of controversy. For that reason plasma lipids and apolipoproteins were compared in three groups of nine patients who had been treated for several months or years with conventional treatment (group I), continuous subcutaneous insulin infusion (CSII, group II) or continuous intraperitoneal insulin infusion (CPII, group III). Plasma cholesterol and apolipoprotein B remained increased on CPII compared with CSII even when similar satisfactory or even tight diabetic control was achieved with both techniques. This study suggests that cholesterol and perhaps apolipoprotein B biosynthesis by the liver is increased in patients treated with CPII compared to those treated with CSII.

[Acute renal failure and hepatitis induced by clometacin]. / Insuffisance rénale aiguë et hépatite à la clométacine.

Various types of allergic accidents have been reported with clometacin (Duperan), a synthetic analgesic introduced in France in 1971. The most prominent is hepatitis in elderly women, with hyperglobulinemia, eosinophilia, autoantibodies and giant multinucleated hepatocytes. The case presented herein concerns a 73-year-old woman who, on two separate occasions after the ingestion of clometacin at recommended dosages, developed at the same time typical acute hepatitis and non-oliguric acute renal failure. The second episode came soon after the medication was inadvertently reintroduced. Both hepatic and renal involvements were fully reversible. A renal biopsy showed predominant lesions of acute interstitial nephritis and tubulonecrosis. Three possible mechanisms are discussed: 1) sensitivity of the kidney to drugs because of preceding angiosclerosis, 2) impaired regulation of renal blood flow because of clometacin provoked decrease of prostaglandin synthesis, and 3) as in the case of nephrotoxicity due to other medications, allergic mechanisms.

[Diabetic cheiroarthropathy. Microcirculatory aspects]. / Cheiroarthropathie diabétique. Aspects microcirculatoires.

Diabetic cheiroarthropathy (DCA) or pseudosclerodermatous hand of the diabetic is characterized by nonpainful limited extension of the proximal metacarpophalangeal and/or interphalangeal joints with spontaneous flexum of the fingers. The mechanism of lesion formation is poorly known but apparently associates neurogenic, vascular and cutaneous phenomena. Fifteen patients with DCA (9 men, 6 women; range 20-74 years) were studied by capillaroscopy, photoplethysmography and skin biopsy. Eleven had type 1 diabetes and 4 type 2 over periods ranging from 1 to 42 years (mean 19.9 years). Diabetic retinopathy was noted 10/15 times, nephropathy 5/15 times and neuropathy of the lower limbs 13/15 times. All patients had at least one of these abnormalities. In capillaroscopy, "Shoal of fish" features of diabetic microangiopathy were found only 4 times, but minor dystrophy was noted in 12 cases. In digital photoplethysmography, a drop in digital systolic pressure or an increase in pulse time was noted in 5 cases. The Hillestad test was less than or equal to 2 in 8 patients. Histological study showed constant dermal collagenous fibrosis in diseased skin, which was also found in normal skin in 6/13 patients. PAS staining showed a thickening of vascular basal membrane 14/15 times in diseased skin and 11/13 times in normal skin. The relation between DCA and microangiopathy is discussed in terms of collagen metabolism abnormalities observed during diabetes.

[Surveillance using vitreo-fluoro-photometry of diabetics treated with an insulin pump, without or with minimal retinopathy. Results after 3 years]. / Surveillance par vitréofluorophotométrie de diabétiques traités par pompe à insuline, avec rétinopathie absente ou minime. Résultats à 3 ans.

In order to appreciate quantitatively the effect of strict metabolic control obtained with continuous insulin infusion, we have carried out a clinical, angiographical and vitreofluorophotometrical follow-up during a mean period of 36 months, on 21 eyes of 11 patients treated with intraperitoneal insulin pump for brittle diabetes. Patients had no (5 patients) or minimal retinopathy (less than 10 microanevrysms, no exsudate or ischemic areas) (6 patients). At the same time, vitreous fluorophotometry was performed on one eye of 15 volunteer patients without any ocular or general pathology. Vitreous fluorophotometry measurements were made with the Fluorotron Master; after substraction of background autofluorescence, and spread function, results are expressed by the level of posterior vitreous penetration by fluorescein. Good metabolic control was achieved during the study (mean +/- S.D. glycemia = 1.47 g/l +/- 0.21, mean +/- S.D. HbA1 = 7.99% +/- 0.84). Final visual acuities were identical to initial ones, there was no angiographical evolution of the retinopathy, and final vitreous fluorophotometry data (OD = 4.19 10(-6)/mn +/- 0.44 S.E.M., OS = 3.28 10(-6)/mn +/- 0.51 S.E.M.) did not statistically differ from the initial data (OD = 3.88 10(-6)/mn +/- 0.49 S.E.M., OS = 4.08 10(-6)/mn +/- 0.64 S.E.M.). On the contrary, volunteers' measurements (2.15 10(-6)/mn +/- 0.26 S.E.M.) were significantly lower than initial (p less than 0.01) and final (p less than 0.05) diabetics' measurements. These results confirm the early breakdown of the blood-retinal barrier during diabetic disease, and would support the notion of a favorable effect of strict metabolic control on early stages of diabetic retinopathy.