Type 2 diabetes mellitus: a disease of the governance of the glucose-insulin system: an experimental metabolic control analysis study.

BACKGROUND AND AIMS: The relatives role of each component of the glucose-insulin system in determining hyperglycemia in type 2 diabetes is still under debate. Metabolic Control Analysis (MCA) quantifies the control exerted by each component of a system on a variable of interest, by computing the relevant coefficients of control (CCs), which are systemic properties. We applied MCA to the intravenous glucose tolerance test (IVGTT) to quantify the CCs of the main components of the glucose-insulin system on intravenous glucose tolerance. METHODS AND RESULTS: We combined in vivo phenotyping (IVGTT/euglycaemic insulin clamp) and in silico modeling (GLUKINSLOOP.1) to compute the CCs of intravenous glucose tolerance in healthy insulin-sensitive (n = 9, NGR-IS), healthy insulin-resistant (n = 7, NGR-IR) and subdiabetic hyperglycemic (n = 8, PreT2DM) individuals and in patients with newly diagnosed type 2 diabetes (n = 7, T2DM). Altered insulin secretion and action were documented in NGR-IR and PreT2DM groups, but only 1st phase insulin secretion was significantly lower in T2DM than in PreT2DM (p < 0.05). The CCs changed little in the nondiabetic groups. However, several CCs were significantly altered in the patients (e.g. CCs of beta cell: -0.75 ± 0.10, -0.64 ± 0.15, -0.56 ± 0.09 and -0.19 ± 0.04 in NGR-IS, NGR-IR, PreT2DM and T2DM, respectively; p < 0.01 by MANOVA), and they could not be corrected by matching in silico nondiabetic and T2DM groups for 1st phase secretion. CONCLUSIONS: Type 2 diabetes is characterized not only by loss of function of the elements of the glucose-insulin system, but also by changes in systemic properties (CCs). As such, it could be considered a disease of the governance of the glucose-insulin system.

ACE genotype and endothelium-dependent vasodilation of conduit arteries and forearm microcirculation in humans.

The ACE gene is a candidate gene for cardiovascular disease. Endothelial dysfunction is considered an intermediate phenotype in the pathogenesis of hypertension and atherosclerosis. We evaluated the role of ACE gene polymorphism in endothelial function of young healthy humans. We assessed ACE genotype (deletion [D]/insertion [I] polymorphism) in 92 young healthy individuals. In 88 of them, endothelium-dependent (flow-mediated) vasodilation and endothelium-independent (nitroglycerin-induced) vasodilation were measured in the common femoral artery and in the brachial (n=84) artery by echo Doppler technique. In 35 subjects, we also applied the forearm perfusion technique to quantify the responses of the forearm vascular bed to 3 increasing doses of 2 endothelium-dependent vasodilators (acetylcholine and bradykinin) and 1 endothelium-independent vasodilator (sodium nitroprusside). The D allele of the ACE gene was associated with a significant blunting (Delta approximately 26%) of endothelium-dependent vasodilation in the femoral artery (P=0.02) but not in the brachial artery (P=0.55) or in the forearm microcirculation (P=0.70 to 0.80). Endothelium-independent vasodilation was unaffected by the ACE genotype. In young healthy humans, the D allele of the ACE gene is associated with selective endothelial dysfunction of the femoral artery. It remains to be determined whether this association discloses a causal role in vascular, particularly peripheral artery, disease.

Assessment of beta-cell function during the oral glucose tolerance test by a minimal model of insulin secretion.

OBJECTIVE: To characterise the performance of beta-cell during a standard oral glucose tolerance test (OGTT). DESIGN: Fifty-six subjects were studied. A minimal analogic model of beta-cell secretion during the OGTT was applied to all OGTTs (see below). The amount of insulin secreted over 120' in response to oral glucose (OGTT-ISR; Insulin Units 120'-1 m-2 BSA) and an index of beta-cell secretory 'force' (beta-Index; pmol.min-2.m-2 BSA) were computed with the aid of the model. In protocol A, 10 healthy subjects underwent two repeat 75 g OGTT with frequent (every 10'-15') blood sampling for glucose and C-peptide to test the reproducibility of OGTT-ISR and beta-Index with a complete or a reduced data set. In protocol B, 7 healthy subjects underwent three OGTTs (50, 100 or 150 g), to test the stability of the beta-Index under different glucose loads. In protocol C, 29 subjects (15 with normal glucose tolerance, 7 with impaired glucose tolerance and 7 with newly diagnosed type 2 diabetes) underwent two repeat 75 g OGTT with reduced (every 30' for 120') blood sampling to compare the reproducibility and the discriminant ratio (DR) of OGTT-ISR and beta-index with the insulinogenic index (IG-Index: Delta Insulin 30' - Basal/Delta Glucose 30' - Basal). In protocol D, 20 subjects (14 with normal glucose tolerance, 5 with impaired glucose tolerance and 1 with newly-diagnosed type 2 diabetes) underwent a 75 g OGTT and an intravenous glucose tolerance test (IVGTT) on separate days to explore the relationships between acute (0'-10') insulin response (AIR) during the IVGTT and beta-index and OGTT-ISR during the OGTT. RESULTS: In all protocols, the minimal analogic model of C-peptide secretion achieved a reasonable fit of the experimental data. In protocol A, a good reproducibility of both beta-index and OGTT-ISR was observed with both complete and reduced (every 30') data sets. In protocol B, increasing the oral glucose load caused progressive increases in OGTT-ISR (from 2.63 +/- 0.70 to 5.11 +/- 0.91 Units.120'-1.m-2 BSA; P < 0.01), but the beta-index stayed the same (4.14 +/- 0.35 vs. 4.29 +/- 0.30 vs. 4.30 +/- 0.33 pmol.min-2.m-2 BSA). In protocol C, both OGTT-ISR and beta-index had lower day-to-day CVs (17.6 +/- 2.2 and 12.4 +/- 2.4%, respectively) and higher DRs (2.57 and 1.74, respectively) than the IG-index (CV: 35.5 +/- 6.3%; DR: 0.934). OGTT-ISR was positively correlated to BMI (P < 0.03), whereas beta-index was inversely related to both fasting and 2 h plasma glucose (P < 0.01 for both). In protocol D, beta-index, but not OGTT-ISR, was significantly correlated to AIR (r = 0.542, P < 0.02). CONCLUSIONS: Analogically modelling beta-cell function during the OGTT provides a simple, useful tool for the physiological assessment of beta-cell function.

Effects of glucosamine infusion on insulin secretion and insulin action in humans.

Glucose toxicity (i.e., glucose-induced reduction in insulin secretion and action) may be mediated by an increased flux through the hexosamine-phosphate pathway. Glucosamine (GlcN) is widely used to accelerate the hexosamine pathway flux, independently of glucose. We tested the hypothesis that GlcN can affect insulin secretion and/or action in humans. In 10 healthy subjects, we sequentially performed an intravenous glucose (plus [2-3H]glucose) tolerance test (IVGTT) and a euglycemic insulin clamp during either a saline infusion or a low (1.6 micromol x min(-1) x kg(-1)) or high (5 micromol x min(-1) x kg(-1) [n = 5]) GlcN infusion. Beta-cell secretion, insulin (SI*-IVGTT), and glucose (SG*) action on glucose utilization during the IVGTT were measured according to minimal models of insulin secretion and action. Infusion of GlcN did not affect readily releasable insulin levels, glucose-stimulated insulin secretion (GSIS), or the time constant of secretion, but it increased both the glucose threshold of GSIS (delta approximately 0.5-0.8 mmol/l, P < 0.03-0.01) and plasma fasting glucose levels (delta approximately 0.3-0.5 mmol/l, P < 0.05-0.02). GlcN did not change glucose utilization or intracellular metabolism (glucose oxidation and glucose storage were measured by indirect calorimetry) during the clamp. However, high levels of GlcN caused a decrease in SI*-IVGTT (delta approximately 30%, P < 0.02) and in SG* (delta approximately 40%, P < 0.05). Thus, in humans, acute GlcN infusion recapitulates some metabolic features of human diabetes. It remains to be determined whether acceleration of the hexosamine pathway can cause insulin resistance at euglycemia in humans.

[Influence of evening primrose oil on blood pressure and the pressor response to angiotensin II in pregnant and non-pregnant rabbits]. / Wplyw oleju z nasion wiesiolka na cisnienie tetnicze krwi i na reakcje presyjna na angiotensyne II u ciezarnych i nieciezarnych królic.

Evening primrose oil was given through a intragastric catheter in dose of 50 mg/kg day for 10 days to pregnant (8 animals) and nonpregnant (8 animals) rabbits. Control groups contained 8 pregnant and 8 nonpregnant animals. In the acute experiment we estimated directly (intraarterially) basal blood pressure and pressor response to angiotensin II (A II). The systolic and diastolic response to A II was significantly lower in pregnant rabbits which received evening primrose oil compared to control group. No significant effect was found in the nonpregnant groups. Basal (before A II) systolic and diastolic blood pressure did not differ between the treated and untreated subject in each group.

[Effect of aminophylline on frequency of blood flow in utero-placental and fetal circulation, on arterial blood pressure and on cardiotocography]. / Wplyw aminofiliny na predkosc przeplywu krwi w krazeniu maciczno-lozyskowym i plodowym, na cisnienie tetnicze krwi oraz na zapisy kardiotokograficzne.

Aminophylline was given (125 mg i.v.) in 24 cases with fetal hypotrophy. Blood flow was measured (Doppler technique) before aminophylline injection, 30 min. and 3-4 hours after. Blood pressure was monitored continuously, CTG was performed many times before and after administration of aminophylline. After administration of aminophylline diastolic blood pressure decreased during 3-4 hours and blood flow in the arcuate artery increased. There were no changes in the blood flow in the umbilical artery and fetal aorta after administration of aminophylline. We didn't observe any changes in CTG before and after administration of aminophylline.

[EPH gestosis or hypertension induced by pregnancy?]. / Gestoza EPH czy nadcisnienie indukowane przez ciaze.

The use of the term "pregnancy induced hypertension" is connected with the use of diagnostic criteria and classification to which this term belongs. These diagnostic criteria have important disadvantages: 1) only diastolic blood pressure is taken into account, 2) oedema is not taken into account, 3) there are only two severity grades, based only on the diastolic blood pressure, 4) "eclampsia imminens" does not exist, 5) "preeclampsia" is when there is elevated diastolic blood pressure and proteinuria, even of low severity both, other symptoms are not taking into account. The applying of such diagnostic criteria can contribute to inadequate management.

Comparison of the effects of Salbupart and Partusisten on the serum levels of insulin, glucose, sodium and potassium in pregnant women.

The effect of tocolytic treatment with Salbupart and Partusisten in imminent premature labour on the serum levels of insulin, glucose, sodium and potassium was studied after 24 hours, and in some cases after 48 and 72 hours from the beginning of intravenous tocolytic treatment. The control group comprised healthy pregnant women receiving no tocolytic treatment. Statistical analysis showed that Salbupart and Partusisten raised the levels of insulin and glucose in the serum in pregnant women, but Salbupart increased more the insulin level and the raised levels of insulin and glucose persisted longer after Salbupart. No effect of these preparations on the serum levels of sodium and potassium in the studied pregnant women was noted.

[Diagnosis and treatment of EPH gestosis at 157 Polish hospitals]. / Jak rozpoznawana i leczona jest gestoza EPH w 157 szpitalach w Polsce.

The average yearly number of deliveries in the 157 hospitals amounts to 294.457. The answers are accompanied by the numbers of hospitals which responded positively to a given question (in per cents). One symptom is enough to diagnose gestosis (90), only edema (82), on edema taken into consideration (3.8). Threshold values: RR 140/90 (68), V Korotkov phase (76), IV phase (21), albuminuria 0.1% (17), 0.2% (15), 0.3% (24), 0.5% (29). Gestosis index (77). Premature termination of pregnancy in serious gestosis often (33), almost always (32), always (21). In eclampsia secondary Cesarean section (46), primary (7), primary when fetus threatened (43). Liquids limited (42), liquids not limited (44), salt limited (73), intensively (12), salt not limited (12). Antihypertensives: hydrazinophtalazine (75), reserpine (53), alphamethyldopa (16), betablockers (13), ganglioplegics (7), diazoxide (1). Others: heparin (7), bufenin (4), other betamimetics (10). In eclampsia MgSO4 (91), benzodiazepins (65), phenothiazines (41), barbiturates (41), chloromethiasol (8), suprameningeal anesthesia (5), dextran (46), albumins (39), saluretics (49). Glycocorticoids when premature delivery in gestosis (56).

[3 classifications of gestosis]. / Trzy klasyfíkacje gestozy.

Three classifications: of the American College of Obstetricians and Gynecologists (ACOG), of the Organization of Gestosis (OG) and of the International Society for Study of Hypertension in Pregnancy (ISSHP) differ among one another in some essential points. According to ACOG the term "preeclampsia" means a state with hypertension and albuminuria or edema, according to ISSHP--hypertension and albuminuria. This may lead to serious misunderstanding as many obstetricians use this term to identify a directly threatening eclampsia attack. But the two classifications do not provide a term for such a condition whereas according to OG this state is identified as threatening eclampsia. The OG and ACOG classifications give a classifications according to the progression of the disease, the ISSHP does not give such a classification. ISSHP does not consider edema as a symptom, ACOG takes it into consideration if it is accompanied by hypertension according to OG the very edema not subsiding after relaxation is enough to diagnose gestosis E. ISSHP has introduced the term "hypertension in pregnancy", but also includes one-symptom form "pregnancy albuminuria" not accompanied by hypertension. Such terms suggest lack of etiological relation between those forms, which has not however been proved. The names of one-symptom forms according to OG "gestosis H" and "gestosis P" do not impose such a relation (it is a classification according to symptoms), but they do not exclude it. Contrary to ACOG and OG, ISSHP gives the level of diastolic blood pressure only.

[Differences in the treatment of EPH gestosis between leading clinics and average hospitals]. / Unterschiede in der Behandlung der EPH-Gestose zwischen den führenden Kliniken und den durchschnittlichen Krankenhäusern.

157 hospitals from Poland with average number of deliveries 294,457 per year answered the questionnaires. In this paper some selected points of the answers are presented; on this basis the treatment of EPH gestosis in average hospitals (a.h.) is compared with the treatment in highly specialized, leading hospitals (l.h.). Similarly as in l.h. the fluid intake in 44% a.h. is not limited but the exact volume of fluid is rarely settled. Similarly to l.h. the salt intake in majority of a.h. is not limited, hydrazinophtalazin, magnesium, diazepam, dextrane and mannitol are widely used. In contrast to l.h. reserpin is still used in 53% of a.h., long-acting barbiturates in 17%, saluretics in 52%, but methyldopa and betablockers rarely (16% and 13%).

[Comparison of the effect of Lasolvan and betamethasone on lung maturity of fetal rabbits]. / Der Vergleich des Einflusses von Lasolvan und von Betamethason auf die Lungenreife fetaler Kaninchen.

8 rabbits received Lasolvan i.v. on day 25, 26 and 27 of pregnancy. 8 rabbits received betamethasone i.m. on 26th and 27th day of pregnancy. The control group received 0.9% NaCl. On day 28 of pregnancy the caesarean section was carried out, the newborn rabbits killed after 45 minutes. In their lungs the lecithin contents was significantly higher in the Lasolvan group than in the betamethasone group and control group, but in the betamethasone group not significantly higher than in the control group. Betamethasone caused in the fetuses the lowering of the body weight, of the wet weight of lungs, of the dry weight lungs and the increase of the pulmonary fluid contents. Lasolvan had no such undiserable effect.