Search

This study aimed to examine brain energy metabolism during moderate insulin-induced hypoglycaemia in Type 1 diabetic patients and healthy volunteers.Type 1 diabetic patients (mean diabetes duration 13 +/- 2.5 years; HbA1c 6.8 +/- 0.3%) and matched controls were studied before, during (0-120 min) and after (120-240 min) hypoglycaemic (approximately 3.0 mmol/l) hyperinsulinaemic (1.5 mU x kg(-1) min(-1)) clamp tests. Brain energy metabolism was assessed by in vivo 31P nuclear magnetic resonance spectroscopy of the occipital lobe (3 Tesla, 10-cm surface coil).During hypoglycaemia, the diabetic patients showed blunted endocrine counter-regulation. Throughout the study, the phosphocreatine:gamma-ATP ratios were lower in the diabetic patients (baseline: controls 3.08 +/- 0.29 vs diabetic patients 2.65 +/- 0.43, p0.01; hypoglycaemia: 2.97 +/- 0.38 vs 2.60 +/- 0.35, p0.05; recovery: 3.01 +/- 0.28 vs 2.60 +/- 0.35, p0.01). Intracellular pH increased in both groups, being higher in diabetic patients (7.096 +/- 0.010 vs. 7.107 +/- 0.015, p0.04), whereas intracellular magnesium concentrations decreased in both groups (controls: 377 +/- 33 vs 321 +/- 39; diabetic patients: 388 +/- 47 vs 336 +/- 68 micromol/l; p0.05).Despite a lower cerebral phosphocreatine:gamma-ATP ratio in Type 1 diabetic patients at baseline, this ratio does not change in control or diabetic patients during modest hypoglycaemia. However, both groups exhibit subtle changes in intracellular pH and intracellular magnesium concentrations.

Objectives Severe hypoglycemia is associated with cognitive decline and dementia in older persons with type 2 diabetes. The role of antidiabetic treatments on severe hypoglycemia is unknown in dementia. The aims were to determine the prevalence of severe hypoglycemic events and investigate associations among severe hypoglycemic and specific antidiabetic treatments (classes of oral agents and types of insulin analogs) in a large sample of nursing home patients with diabetes according to dementia status. Design Cross-sectional observational study. Setting A total of 150 nursing homes across Italy. Participants A total of 2258 patients with type 2 diabetes (dementia = 1138, no dementia = 1120). Measurements Diagnosis of dementia before nursing home admission. Data were collected regarding functional status, glycemic control, antidiabetic treatments, comorbidities, and biochemical and clinical measurements. Logistic regression models with severe hypoglycemia as the dependent variable were used to test associations with antidiabetic agents. Results Patients had a mean age (SD) of 82 (8) years, body mass index (BMI) of 25.4 (4.8), fasting plasma glucose (FPG) of 7.5 (3.0) mmol/L, postprandial glucose (PPG) of 10.3 (3.6) mmol/L, HbA1c of 7.1% (54 mmol/L), and impairments in activities of daily living (ADLs) of 3.7 (2.1). Severe hypoglycemia was more prevalent in patients with dementia (18%) compared with patients without dementia (8%). Patients with dementia were older, showed greater ADL impairments, greater number of comorbidities, lower FPG, and higher PPG compared with those without dementia. Adjusted logistic regression models in patients with dementia showed that rapid- and long-acting insulin analogs were associated with reduced odds ratio (OR) (OR 0.333; 95% confidence interval [CI] 0.184–0.602; OR 0.248, 95% CI 0.070–0.882, respectively), whereas sulphonylureas and combined metformin + sulphonylurea were associated with increased ORs (OR 8.805, 95% CI 4.260–18.201; OR 6.639; 95% CI 3.273–14.710, respectively) of experiencing severe hypoglycemia. No correlations were found in patients without dementia. Conclusion In older nursing home patients with type 2 diabetes, severe hypoglycemia was significantly higher in dementia. Our findings suggest that sulphonylureas should be used with caution, whereas rapid- and long-acting insulin analogs seem safer.

(Cell 153, 747–758; May 9, 2013)In this article, we claimed that Angptl-8, which we termed betatrophin and is also referred to in the literature as TD26, RIFL, C19orf80, and Lipasin, was the agent by which the insulin antagonist S961 induces robust β cell replication in mice. Gusarova et al., in a Matters Arising article, subsequently showed that targeted Angptl-8/betatrophin overexpression in mice increases blood triglycerides but does not induce β cell growth (Cell, 2014, 159, 691–696). When we repeated our original experiments with a larger number of mice, we also failed to observe β-cell expansion upon Angptl-8/betatrophin overexpression and reported these results in a Correspondence (Cell, 2014, 159, 467–468). We have subsequently repeated a series of blinded experiments with the Kushner lab and have now determined conclusively that our conclusion that Angptl-8/betatrophin causes specific β cell replication is wrong and cannot be supported (PLoS One, 2016, 11, e0159276). Therefore, the most appropriate course of action is to retract the paper. We regret and apologize for this mistake.

In this issue of Cell, Gusarova et al. (2014) show that deletion of ANGPTL8 in mice does not affect the compensatory proliferation of pancreatic beta cells in response to insulin resistance induced by a high-fat diet or treatment with the insulin antagonist S961. They also show that overexpression of human ANGPTL8 in mouse liver leads to elevated serum triglyceride levels but not significant pancreatic beta cell proliferation. They conclude that ANGPTL8 (also called betatrophin [Yi et al., 2013]/RIFL [Ren et al., 2012]/lipasin [Zhang, 2012]) does not control pancreatic beta cell expansion.

Diabetic levels of the synalbumin insulin antagonist were found in 30% of a group of 50 women who had had unexplained intrauterine foetal deaths. Four per cent of the control group had similar levels of antagonism. Previous reports of an increased foetal mortality in potentially diabetic women were confirmed.

Aucun effet diabetogene ni hyperglycemiant aigu de l'hydrochlorothiazide (HCT) n'a ete decele par des determinations de la glycemie a jeun (avant et 2–8 h apres l'administration d'HCT) et de la tolerance au glucose effectuees chez des rats normaux et des rats sensibilises a un effet diabetogene par une pancreatectomie subtotale ou par l'injection d'une dose subdiabetogene d'alloxane, au cours d'un traitement de 6 semaines par des doses de 50–200 mg/kg · jour d'HCT p. o. — De fortes doses (plus de 3 ml/kg) de N-monomethylamide de l'acide acetique (NMMAA), solvant qui fut utilise dans la preparation d'une solution injectable commerciale d'hydrochlorothiazide, ont par contre exerce des effets diabetogenes tres marques chez le rat. Toute dose lethale de NMMAA a induit chez cet animal un syndrome diabetique, c'est-a-dire une hyperglycemie progressive avec aeido-cetose metabolique, ressemblant au syndrome diabetique aigu induit par l'injection d'une forte dose de serum anti-insulinique. — Des fractions de doses lethales administrees quotidiennement pendant plusieurs jours ont exerce des effets diabetogenes et lethaux cumulatifs: la substance ou l'un de ses metabolites toxiques apparait persister longtemps dans l'organisme du rat.-Des doses sublethales de NMMAA ont induit une hyperglycemie reversible d'une duree de quelques jours. Nous avons donc constate que le diabete produit par le NMMAA etait soit transitoire soit lethal. Aucun signe de toxicite ne s'est manifeste au cours d'un traitement de 6–8 mois par des doses inferieures a 0,5 ml/kg · jour. — Chez les rats intoxiques par une dose lethale de NMMAA, une correlation positive tres significative a ete notee entre les valeurs seriques d'insuline immuno-reactive (IRI) et les valeurs de glycemie. Bien qu'ils aient ete, a glycemie comparable, superieurs a ceux constates dans le serum de rats normaux apres surcharge de glucose, les taux d'IRI se trouvant dans le serum des rats intoxiques n'ont pas ete en mesure de s'opposer a l'elevation reguliere de la glycemie jusqu'a la mort. — L'effet hypoglycemiant d'insuline cristalline porcine est apparu inhibe chez les rats intoxiques par le NMMAA, compare a l'effet observe chez des rats normaux ou en diabete alloxanique.-Utilisant l'augmentation de l'oxydation du premier atome de carbone du glucose-l-C14 par le tissu adipeux epididymaire du rat, in vitro, comme index metabolique de l'activite insulino ide du serum (ILA), nous n'avons pas constate, dans le serum des rats intoxiques et en etat de forte hyperglycemie, des taux d'ILA significativement superieurs a ceux presents dans le serum de rats temoins a jeun. Alors que, chez des rats normaux, la fraction de l'ILA serique supprimable par serum anti-insulinique (SILA) s'elevait fortement, comme l'IRI, au cours de l'hyperglycemie induite par une surcharge de glucose, cette fraction SILA n'est pas apparue en quantites decelables dans le serum des animaux intoxiques. L'IRI serique de ces animaux n'a donc semble-t-il pas exerce d'effet «insulin-like» sur le tissu adipeux isole de rat normal.-Les faits observes amenent a la conclusion que les rats intoxiques par le NMMAA inactivent et l'insuline endogene et l'insuline exogene. Bien qu'ayant perdu son activite metabolique, l'insuline endogene inactivee reste immunologiquement competente.

Insulin resistance is currently believed to be associated with insulin-neutralizing substances in the blood. Lowell (1), employing the mouse convulsion assay for insulin, has shown that the injection of mixtures of insulin and serum from insulin-resistant diabetic patients into mice caused a significantly smaller incidence of convulsive symptoms than the injection of the same amounts of insulin alone. He points out, however, that the quantitative interpretation of these experiments is difficult because of the variations of the response of the animals to insulin and the nonspecific effects of the injection of serum. It would be desirable, therefore, to employ a method for the determination of insulin-inactivating properties of serum which does not involve the administration of insulin-serum mixtures to the intact animal. In the course of our recent work on the chemical combination of insulin with the rat diaphragm (2, 3) it became apparent that this technique would provide a method for the detection of insulin-inactivating substances in any solution. Accordingly, we have tested serum from normal, diabetic, and insulin-resistant subjects and found, in confirmation of the results of Lowell, that serum from insulin-resistant patients has the property of opposing the action of insulin.

Albumin prepared from serum of diabetic patients inhibits the effect of insulin on rat diaphragm muscle but not on their epididymal fat pads when injected intravenously to make a foreign protein concentration of 3.8 g/100 ml in the plasma of the rat. At this concentration, albumin from normal subjects had no insulin inhibitory effect on either tissue. — These observations confirm, underin vivo conditions, that diabetic albumin is more antagonistic to insulin than albumin prepared from normal subjects.

The incidence of excessive synalbumin antagonism has been studied in a small randomly selected population survey. One hundred and forty-two volunteers were tested, 70 men and 72 women, between the ages of 18 and 45 years, none of whom had overt diabetes. — Fifteen men (21%) and 26 women (36%) were synalbumin positive with an overall incidence of 28%, which is not dissimilar to the previously reported incidence of 25%.

Patients with essential diabetes including prediabetes have more synalbumin antagonism to insulin than normal subjects or patients with “pancreatic” diabetes, e.g. after pancreatectomy. Thus excessive synalbumin antagonism (synalbumin positive) can be regarded as a biochemical marker to ascertain whether a given person is constituted as an essential diabetic-without reference to carbohydrate intolerance.-On this premise, the genetic transmission of essential diabetes has been examined by studying the relatives of essential diabetics. The results strongly suggest that excessive synalbumin antagonism is inherited as an autosomal “dominant” character.-Ninety-seven members of nine families were studied, 39 were synalbumin negative whereas 58 were synalbumin positive, but only 16 of these latter have overt carbohydrate intolerance. A further three have spontaneous hypoglycaemia whereas the remainder are quite asymptomatic. These observations suggest that overt carbohydrate intolerance is relatively uncommon or will be a late event in many people constituted as essential diabetics.

DURING the investigation of the insulin antagonism associated with human serum albumin1, ‘Visking’ tubing (Visking Corporation, Chicago, U.S.A,) was used for ultrafiltration and dialysis of protein solutions. The tubing itself has since been found to give rise to a substance which antagonizes insulin and which appears in the following circumstances: (1) When distilled water is ultrafiltered through 7-ft. of heavy grade ‘Visking’ tubing (27/32 in. inflated diameter) supported by ‘Terylene’ net, under a negative pressure of 40–50 cm. mercury, over a period of three days. (2) When 7 ft. light grade ‘Visking’ tubing (18/32 in.) is filled with water and suspended in changes of distilled water for 2–7 days, that is, used as dialysis tubing.

Da Guanidinosuccinsaure in der Uramie akkumuliert, wurde angenommen, dass dieses Stoffwechselprodukt bei Niereninsuffizienz die bekannte Glukoseintoleranz verursachen konnte. In-vitro-Versuche am Rattenzwerchfell haben diese Hypothese jedoch nicht bestatigen konnen, da Guanidinosuccinsaure in der Konzentration von 3 mg/100 ml keinen Einfluss auf die basale oder insulinstimulierte Glucoseaufnahme durch dieses Gewebe zeigte.

Studies on ultrafiltrates of the plasma of normal and diabetic subjects have shown that a polypeptide of similar characteristics to the growth-hormone-derived polypeptide In-G is present in higher concentrations in diabetic subjects, thus indicating a possible role in the pathogenesis of diabetes mellitus. The polypeptide is absent from the plasma of hypophysectomized diabetic patients.