Incidence, diagnostics and treatment algorithm of nerve lesions after traumatic shoulder dislocations: a retrospective multicenter study.

BACKGROUND: The shoulder is the joint most prone to dislocating in the human body and accounts for 45% of all dislocations. In addition to ruptures of the soft tissue and bony injuries, lesions to vascular structures as well as the brachial plexus and its corresponding nerves might occur. With an incidence of up to 65%, nerve lesions are frequently reported after shoulder dislocations. The aim of this study is to obtain information on epidemiology, diagnostics, treatment and duration until remission or late sequelae after shoulder dislocation and concomitant nerve injury in a large patient cohort. METHODS: The patient cohort consisted of 15,739 patients from three centres who had sustained a shoulder dislocation. All patient files were searched for concomitant injury of the brachial plexus or its corresponding nerves. For epidemiological data analysis, demographic data, clinical follow-ups, electromyography and nerve conduction velocity were evaluated. RESULTS: In total, 60 patients (32 males, 28 females) with a mean age of 60 years (range 19-88 years) met the inclusion criteria. In the majority of patients (n = 51), the trauma mechanism was a trivial fall on the outstretched arm. The most frequent dislocation direction was anterior-caudal in 61.6%, followed by strictly caudal in 16.6%. The brachial plexus was injured in 46 patients (76.6%) and isolated nerve damage was documented in 14 patients (23.3%). Electroneurographic examinations were performed in less than half of the patients (38.3%). CONCLUSION: A combination injury of shoulder dislocation and plexus lesion may occur at any age and sometimes has a poor outcome. Electroneurographic examinations should be implemented when managing these patients as a cost-effective and supportive examination. LEVEL OF EVIDENCE: Level IV, retrospective study.

ACL reconstruction with femoral and tibial adjustable versus fixed-loop suspensory fixation: a retrospective cohort study.

BACKGROUND: Cortical suspensory fixation (CSF) devices gain more and more popularity as a reliable alternative to interference screws for graft fixation in anterior cruciate ligament (ACL) reconstruction. Adjustable-loop fixation may be associated with increased anterior laxity and inferior clinical outcome. The purpose of the study was to compare anterior laxity and clinical outcome after minimally invasive all-inside ACL reconstruction using an adjustable-loop (AL) to a standard technique with a fixed-loop (FL) CSF device. METHODS: Patients who underwent primary single-bundle ACL reconstruction with a quadrupled hamstring autograft at a single institution between 2012 and 2016 were reviewed. In the AL group minimally invasive popliteal tendon harvesting was performed with an all-inside approach (femoral and tibial sockets). In the FL group a traditional anteromedial approach was used for tendon harvesting and a femoral socket and full tibial tunnel were drilled. An objective clinical assessment was performed with Telos x-rays and the International Knee Documentation Committee (IKDC) Objective Score. Patient-reported outcomes (PRO) included the IKDC Subjective Score, the Lysholm Knee Score, the Knee Injury and Osteoarthritis Score (KOOS) and the Tegner Activity Scale. RESULTS: A total of 67 patients were enrolled in this retrospective study with a mean follow-up of 4 (± 1.5) years. The groups were homogenous at baseline regarding age, gender, and the time to surgery. At follow-up, no statistically significant differences were found regarding anterior laxity (AL: 2.3 ± 3 mm vs. FL: 2.3 ± 2.6 mm, p = 0.981). PRO scores were comparable between the AL and FL groups (IKDC score, 84.8 vs. 88.8, p = 0.185; Lysholm 87.3 vs. 89.9, p = 0.380; KOOS 90.7 vs. 91.4, p = 0.720; Tegner 5.5 vs. 6.2, p = 0.085). The rate of saphenous nerve lesions was significantly lower in the AL group with popliteal harvesting of the tendon (8.3% vs. 35.5%, p = 0.014). CONCLUSION: The use of an adjustable-loop device on the femoral and tibial side led to similar stability and clinical results compared to a fixed-loop device.

Long-term results after primary augmented repair of proximal tears of the anterior cruciate ligament with the Kennedy-LAD - Does it work?

BACKGROUND: The purpose of this study was to objectively evaluate the clinical functionality of the knee joint 30 years after surgical augmentation of the ACL with the "Kennedy Ligament Augmentation Device ®" (Kennedy LAD®). METHODS: The patient collective consisted of 41 patients with an average age of 59.51 years (±10.18 standard deviation). Included were all patients treated operatively with a Kennedy LAD® augmented reattachment of the ACL at the Department of Trauma Surgery between 1983 and 1985. The state of the knee joint was evaluated with the following measures: Knee injury and Osteoarthritis Outcome Score, Lysholm Score, Short Form (36) Health Survey, International Knee Documentation Committee Score (IKDC, objective + subjective form) and Tegner Activity Scale. RESULTS: Seven patients (17%) sustained a re-rupture of the Kennedy LAD® augmented ACL after a mean time of 16.28 years. Five of them underwent revision surgery. Another four patients (9.76%) showed an ACL insufficiency in clinical examination. The average IKDC Score was 74.14 ±â€¯16.62, the average Lysholm Score was 86.83 ±â€¯14.10, the average Tegner Activity Scale was 4.34 ±â€¯1.11, and the average Knee injury and Osteoarthritis Outcome Score was 86.25 ±â€¯11.64 at final follow-up. The mean Kellgren Lawrence Score of the operated knee was 2 ±â€¯0.71. CONCLUSION: An overall good outcome 30 years after primary ACL augmented repair with the Kennedy LAD® with an implant survival rate of 73% could be reached. These results therefore support the trend of ACL augmentation in selected cases. LEVEL OF EVIDENCE: Retrospective study, Level IV.

The use of the LARS system in the treatment of AC joint instability - Long-term results after a mean of 7.4 years.

BACKGROUND: The acromioclavicular (AC) joint is of great importance for shoulder stability and one of the most frequently injured regions of the shoulder. HYPOTHESIS: AC joint reconstruction with the ligament augmentation & reconstruction system (LARS™) leads to a good-to-excellent outcome at long-term follow-up. PATIENTS AND METHODS: This study was performed as a retrospective single-centre data analysis of a level-I trauma centre. All patients treated operatively for an acute AC dislocation with the LARS™ between 2003 and 2013 were included. RESULTS: The study group consisted of three female (6%) and 44 male patients (94%) with an average age of 37 years and a minimum follow-up of two years. The overall mean clinical outcomes at latest follow-up were: Constant 93, DASH 2.64, ASES 96, SST 97, UCLA 34 and VAS 0.4-representing a good-to-excellent outcome in all patients. Overall, 45 patients (96%) reported to be very satisfied with the achieved result at latest follow-up. In five patients, (11%) complications occurred during the follow-up period, requiring surgical revision in four of the five patients (80%). CONCLUSION: AC joint reconstruction with the LARS™ achieves good-to-excellent clinical and functional outcomes at long-term follow-up with a surgical revision rate of 8.5%. LEVEL OF EVIDENCE: Retrospective follow-up study, case series, level IV.

Efficacy of pulsatile versus continuous insulin administration on hepatic glucose production and glucose utilization in type I diabetic humans.

To evaluate the role of pulsatile insulin administration, hepatic glucose production (HGP) and utilization were studied in type I diabetic patients in the fasting state and during a euglycemic insulin (1 mU X kg-1 X min-1 i.v.) clamp with continuous and pulsatile insulin administration. In the latter study, insulin was infused at twice the continuous rate with 3-min-on/7-min-off intervals, thereby reducing total insulin delivery by 40%. The restraining effect of pulsatile insulin on basal HGP (1.91 +/- 0.35 mg X kg-1 X min-1) was equipotent to continuous insulin exposure (1.80 +/- 0.17 mg X kg-1 X min-1). During the insulin-clamp studies, HGP was equally suppressed by pulsed (0.62 +/- 0.12 mg X kg-1 X min-1) as by continuous insulin infusion (0.63 +/- 0.12 mg X kg-1 X min-1). Insulin-stimulated glucose utilization was not significantly altered in either study (2.55 +/- 0.27 vs. 2.92 +/- 0.23 mg X kg-1 X min-1). When in further studies the total insulin dose given during the pulsatile study was infused continuously (0.6 mU X kg-1 X min-1), HGP in the basal state and residual HGP during the insulin-clamp study were 25-30% higher than in the pulsatile experiments, whereas glucose utilization was not significantly different. In conclusion, by reducing total hormone delivery by up to 40%, but given in a pulsatile fashion, insulin is equally potent in controlling HGP as continuous insulin administration. This greater efficacy of pulsatile exposure in suppressing HGP is accompanied by an equipotent effect on glucose utilization.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of stress hormones on splanchnic substrate and insulin disposal after glucose ingestion in healthy humans.

To compare cortisol and epinephrine action on oral glucose tolerance, healthy humans were infused with either cortisol (0.1 mg X kg-1 X h-1), epinephrine (5.4 micrograms X kg-1 X h-1), or saline before and after a 75-g glucose load, thereby elevating the respective plasma hormone concentrations into the pathophysiologic range. In the basal state, epinephrine increased arterial concentrations of glucose, beta-hydroxybutyrate, and free fatty acids (FFA) as well as splanchnic output of glucose and beta-hydroxybutyrate and splanchnic FFA more than cortisol. Postprandially, C-peptide release and hyperinsulinemia were blunted by epinephrine initially and increased less thereafter than during cortisol infusion. The rise in arterial glucose after glucose ingestion as calculated by the area under the curve was more marked (P less than .01) after epinephrine [( 1.90 +/- 0.08 M) 150 min] and cortisol [( 1.41 +/- 0.05 M) 150 min] than in the control study [( 1.07 +/- 0.04 M) 150 min]. In parallel, the stress hormones induced an almost identical 24 and 31% rise in mean splanchnic glucose output versus control values (normal, 44.8 +/- 2.5; cortisol, 55.3 +/- 3.3; epinephrine, 58.9 +/- 6.9 g/150 min). The associated rise in arterial concentrations and splanchnic output of insulin above control values was considerably greater during cortisol but unchanged during epinephrine exposure. Epinephrine but not cortisol induced a rise versus the control study in splanchnic uptake of lactate and FFA, as well as in pyruvate output, whereas plasma beta-hydroxybutyrate and acetoacetate remained unchanged. The postprandial splanchnic glucose output-to-splanchnic C-peptide output ratio did not differ from normal during epinephrine but was reduced (P less than .01) during cortisol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the biologic actions of biosynthetic human insulin in vitro and in diabetic man.

This preliminary study was designed to determine whether biologic action of biosynthetic human insulin (BHI) in vitro and its antigenicity in man equals that of various insulins of pancreatic origin. Testing the biologic action of BHI, pancreatic human insulin (PHI), and pancreatic pork insulin (PCPI) on glucose uptake by the rat hemidiaphragm and adipose tissue, identical efficacy for the insulins on a unit per unit basis was observed. Furthermore, a comparable impairment of insulin action was seen under the detrimental conditions of a hyperosmolal state. In an insulin-dependent diabetic female patient with cutaneous insulin hypersensitivity, BHI displayed the same antigenicity as PHI and PCPI. From these data we conclude tht BHI, both in vitro and in vivo, exhibits the same biologic properties as pancreatic insulin, and that it is reasonable to continue extensive testing of BHI in man, since identical metabolic effects and immunologic reactions are to be anticipated as with purified pancreatic insulin preparations of human or animal origin.

Superior efficacy of pulsatile versus continuous hormone exposure on hepatic glucose production in vitro.

To elucidate the potency of continuous vs. intermittent exposure to hormonal stimuli, hepatic glucose production of isolated perfused rat livers was monitored in response to glucagon and insulin infusion. Using a nonrecirculating perfusion system, continuous exposure to glucagon (35 pM) induced a rise in hepatic glucose production from basal 0.33 +/- 0.03 mmol/(96 min X 100 g BW) to 0.65 +/- 0.02 mmol/(96 min X 100 g BW), while intermittent exposure (3 min on/off intervals; total dose 50%) to the same glucagon concentration elicited an almost identical rise in hepatic glucose production to 0.59 +/- 0.12 mmol/(96 in X 100 g BW). Insulin (100 mU/liter) given continuously and intermittently (3 min on/off intervals) inhibited glucagon-stimulated (70 pM) hepatic glucose production to the same extent, i.e. by 37.4% and 41.1%, respectively. Doubling the off period to 6 min and thereby reducing the total hormone dose to 33% did not diminish insulin's suppressive effect on glucagon-stimulated hepatic glucose release (34.6%). When the latter infusion protocol was applied with insulin at 300 mU/liter, hepatic glucose production during the first 40 min of glucagon infusion was more restrained (P less than 0.01) than during continuous delivery of 100 mU/liter, although the same amount of insulin was infused per period of time. In parallel, glucagon-stimulated cAMP release was similarly suppressed by insulin in all experiments. From this we conclude that the effect on hepatic glucose production of pulsatile administration of glucagon as well as of insulin, depending on the applied time interval of hormone exposure, is equipotent or even superior to the respective hormones' continuous infusion even if the hormone load is significantly reduced.

Lifelong sequential changes in glucose tolerance and insulin secretion in genetically obese Zucker rats (fa/fa) fed a diabetogenic diet.

Life-long sequential changes in glucose tolerance and insulin secretion were investigated in genetically obese Zucker rats (fa/fa) fed a diabetogenic diet rich in lard and sucrose. Comparisons were made with lean littermates (Fa/-) receiving normal chow diet. At 3-month intervals, seven to nine lean and obese rats had two permanent venous catheters implanted, allowing stress- and pain-free sampling of blood before, during, and after substrate administration. Intravenous glucose, iv arginine, and oral glucose tolerance were tested. The obese rats progressively developed hyperglycemia and severe hyperinsulinemia; their basal glycemia reached 8.8 +/- 1.1 vs. 5.8 +/- 0.2 mmol/liter in the lean rats at 46 weeks of age; respective insulinemia was 287.7 +/- 61.9 and 18.1 +/- 2.8 mU/liter (mean +/- SD). In the obese rats a distinct loss in glucose tolerance was seen with progression of age in spite of rising stimulated insulin secretion, which suggests progressive development of insulin resistance without exhaustion of B-cell secretory capacity. Absence of insulin deficiency was also suggested by immunohistochemical staining of pancreatic tissue specimens from obese rats, which showed large populations of insulin-containing cells. Like the obese animals, lean rats exhibited a decrease in insulin sensitivity with age. Relating basal individual glycemia and insulinemia, a rise by 1 mmol/liter in glycemia was associated with a 8.8-fold rise in basal insulinemia in lean rats, but only with a 1.8-fold increase in obese rats. Similar correlations for stimulated glycemia and insulinemia suggest impaired glucose sensitivity of pancreatic B-cells in obese vs. lean rats. In conclusion, hyperglycemia and hyperinsulinemia in insulin-resistant obese Zucker rats on a diabetogenic diet are not characterized by quantitatively deficient B-cell secretory capacity, but, rather, by impaired B-cell sensitivity to glucose with qualitatively intact regulation of glycemia and insulinemia at elevated plasma concentrations.

Interaction of sympathomimetics and insulin with hepatic glucose production by isolated perfused rat livers: effects of continuous versus pulsatile infusion.

To elucidate the efficacy of continuous vs. intermittent exposure to epinephrine, phenylephrine, and insulin, hepatic glucose production was monitored in isolated perfused rat livers (means +/- SE, n = 6 each). To this end livers of fed rats were perfused with 5 mM glucose Krebs-Ringer buffer in a nonrecirculating system. Using this model it was shown that intermittent exposure (3 min on/off period, dose reduction -50%) to epinephrine (0.4 microM, alpha + beta-agonist) and phenylephrine (5 microM, alpha-agonist) elicited an almost identical rise in hepatic glucose production [epinephrine: 0.72 +/- 0.08 mmol/(86 min X 100 g BW); phenylephrine: 0.68 +/- 0.07 mmol/(86 min X 100 g BW) as their continuous administration (epinephrine: 0.78 +/- 0.06 mmol/(86 min X 100 g BW); phenylephrine: 0.74 +/- 0.09 mmol/(86 min X 100 g BW)]. Inhibition by insulin (100 mU/liter) given either continuously or intermittently (3 min on/off intervals; dose reduction -50%) was equipotent for epinephrine- and phenylephrine-stimulated hepatic glucose production. When the off period was doubled to 6 min, thereby reducing the total insulin dose to 33%, no significant suppression of epinephrine- and phenylephrine-stimulated hepatic glucose production was observed. From this we conclude that 1) the effect on hepatic glucose production of pulsatile (3 min on/off, dose reduction 50%) and continuous administration is equipotent for the respective action of epinephrine, phenylephrine as well as of insulin; and 2) insulin is more effective (P less than 0.02) in inhibiting hepatic glucose production stimulated by an alpha-agonist (phenylephrine; 5.0 microM) than in counteracting alpha + beta-agonist action (epinephrine; 0.4 microM). The characteristics of hepatic glucose release as stimulated by alpha- and/or beta-adrenergic agonists and its inhibition by continuously or intermittently infused insulin were simulated and described by a computer model. Thereby, no qualitative difference could be demonstrated in alpha- vs. beta-adrenergic agonists action on stimulated hepatic glucose production.

Contribution by the glycogen pool and adenosine 3',5'-monophosphate release to the evanescent effect of glucagon on hepatic glucose production in vitro.

To elucidate in vitro the transience of glucagon-induced hepatic glucose release, the effects of glucagon on hepatic glucose production and cAMP release were evaluated in the isolated rat liver preparation perfused by a nonrecirculating system. Glucagon was added to the infusate in stepwise increasing concentrations at 0, 60, and 100 min to give final concentrations of 2.5 X 10(-11), 10(-9), and 5 X 10(-8) M, respectively. Glucagon at 2.5 X 10(-11) M caused cAMP release [basal (mean +/- SD), 11.2 +/- 3.0 pmol/(min X 100 g BW)] to rise rapidly and plateau at 23.3 +/- 7.0 pmol/(min X 100 g BW), whereas hepatic glucose production [basal, 3.7 +/- 1.6 mumol/(min X 100 g BW)] increased only transiently to a maximum of 15.3 +/- 3.1 mumol/(min X 100 g BW) and fell thereafter. The enhanced cAMP release during the consecutive glucagon infusion was accompanied by a transient rise in hepatic glucose production during the second, but not during a third, glucagon infusion. When 3-isobutyl-1-methylxanthine, a potent phosphodiesterase inhibitor, was added to the perfusion medium (0.5 mM), the cAMP response to 2.5 X 10(-11) M glucagon was enhanced [247 +/- 124 pmol/(min X 100 g BW)] as was hepatic glucose production (+ 21%; P less than 0.05). Further augmentation of the glucagon concentration was followed by an increase in hepatic cAMP, but not glucose, release. When glucagon infusion (2.5 X 10(-11) M) was repeated with a glucagon-free period of 30 min in between, no stimulation of cAMP and consecutive glucose release was found during the second period. However, when the second glucagon dose was increased to 10(-9) M, glucose and cAMP release were again stimulated to the same extent as in experiments with no glucagon-free period in between. We conclude that the size of the glycogen pool and the cAMP concentration directly modulate hepatic glucose production and are responsible for evanescent glucagon action. This mechanism can be described by computer simulation.

Glucose metabolism in noninsulin-dependent diabetic patients with experimental hyperthyroidism.

Hyperthyroidism is known to further impair carbohydrate metabolism in diabetic patients. In the present study we examined in noninsulin-dependent (type 2) diabetic patients the effect of T3-induced hyperthyroidism on glucose utilization and endogenous glucose production by means of the hyperinsulinemic and hyperglycemic clamp technique in combination with [3H]3-glucose kinetic analysis. Administration of T3 for 1 week increased the mean serum T3 concentration from 1.0 +/- 0.1 (SEM) to 4.1 +/- 0.2 ng/ml, and the mean fasting plasma glucose from 8.7 +/- 0.7 to 9.9 +/- 0.9 mmol/liter. Basal hepatic glucose production (HGP) rose from 3.23 +/- 0.23 to 3.98 +/- 0.25 mg/kg X min, whereas basal MCR of glucose (MCRG) increased only slightly from 2.12 +/- 0.24 to 2.30 +/- 0.14 ml/kg X min. When the plasma insulin concentration was acutely raised and maintained at 82 +/- 8 microU/ml (hyperinsulinemic clamp study), HGP decreased to 0.71 +/- 0.29 mg/kg X min and MCRG increased to 3.16 +/- 0.47 ml/kg X min. After T3 administration suppression of HGP by insulin was reduced (1.55 +/- 0.37 mg/kg X min), but at the same time MCRG was only slightly affected (3.64 +/- 0.54 ml/kg X min). In the hyperglycemic clamp study the plasma glucose concentration was maintained 7 mmol/liter above the individual fasting level. MCRG was again slightly higher after T3 administration (1.98 +/- 0.18 vs. 1.66 +/- 0.15 ml/kg X min), but insufficient to completely compensate for the higher residual HGP at the hyperthyroid as compared to the euthyroid state (2.42 +/- 0.24 vs. 1.45 +/- 0.36 mg/kg X min). Thus, deterioration of metabolic control in noninsulin-dependent diabetic patients by hyperthyroidism is due primarily to enhancement of basal HGP and its reduced suppressibility by insulin and glucose.

Contribution of plasma proteins to muscular de novo synthesis of glutamine.

Amino acid balance across the muscle bed is known to be negative in the postabsorptive state. The explanation for such permanent amino acid loss by muscle tissue has to be sought in either its proteolytic breakdown, that of plasma polypeptides and proteins, increased rate of amino acid transport out of the cell, or de novo synthesis of amino acids. To evaluate the contribution of plasma proteins to muscle amino acid release in vitro, hindquarters of 48-hour-fasted rats were perfused with 6 mmol/L glucose Krebs-Ringer buffer containing 20% human erythrocytes and albumin or gamma-globulin at concentrations of 5%, 0.5%, and 0%, respectively. To maintain oncotic pressure, plasma proteins were replaced in the latter protocol by 60-kd dextran. Perfusion for 60 minutes without plasma proteins resulted in a fall in amino acid release by 32% and 23%, respectively, compared with amino acid concentrations in the venous hindquarter effluent during infusion of 5% albumin and gamma-globulin, respectively. The impairment of amino acid release was primarily due to decrease in glutamine generation, which dropped from 327.4 +/- 47.3 and 323.0 +/- 35.7 to 211.9 +/- 22.0 mumol/L, respectively (means +/- SE, n = 7). The present data suggest that the apparent negative nitrogen balance observed across the muscle bed in vitro is not caused solely by muscle degradation but also, to a considerable extent, by proteolytic breakdown of "arterial" plasma protein, whose role in in vivo experiments remains to be established.

Effect of stress hormones on transsplanchnic balance of exogenous amino acid in healthy man.

The effect of stress hormones on transsplanchnic balance of basal and infused amino acids (AA: Val,Met,Ile,Leu,Phe,Lys,His) was investigated in healthy men without and with added epinephrine (EPI) and dexamethasone (DEX). Concentrations of AA and blood glucose were measured in arterial and hepatic venous blood before and after primed-continuous (t = 120 minutes) AA infusion without (group I: controls; n = 6, 24 +/- 3 years), and with intravenous (IV) EPI infusion (group II: 6 micrograms/min, t = -75 to 120 minutes; n = 6, 26 +/- 5 years) or oral DEX pretreatment (group III: 6 mg/d for 2 days; n = 7, 26 +/- 3 years). In the absence of exogenous AA, EPI was demonstrated to increase estimated hepatic plasma flow (EHPF, mL/min: 1,019 +/- 133 [mean +/- SD] v 737 +/- 153; P less than .01), splanchnic output of glucose (SGO), and splanchnic uptake of total AA (nmol/kg.min: 4,657 +/- 2,014 v 2,802 +/- 704; P less than .05), of Gln (+78%) and of Gly (+100%). DEX did not affect EHPF or SGO, but doubled basal splanchnic AA uptake (5,446 +/- 3,635 nmol/kg.min) and increased that of Gln by 110%. Following AA administration, total splanchnic AA uptake was consistently increased (group I, 8,577 +/- 2,380; II, 8,957 +/- 3,714; III, 10,757 +/- 2,689 nmol/kg.min) as was splanchnic Gln uptake, both of which did not differ versus controls following EPI or DEX exposure. However, metabolic clearance rate (MCR, L/min) of infused AA was elevated by 40% (Met) to 85% (Leu) versus controls in subjects receiving EPI, but unchanged in those receiving oral DEX.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of indomethacin on hepatic glucose production in vitro: the impact of hepatic glycogen content.

The effect of indomethacin (IND) on glucagon-induced hepatic glucose production (HGP) was studied in the isolated perfused livers of rats. Addition of IND (0.2 mM) to the perfusion medium had no effect on glucagon-stimulated HGP when compared to control experiments without added IND (1.02 +/- 0.17 vs. 1.00 +/- 0.26 mmol per (120 min X 100 g b.w.), respectively; NS). Intravenous pretreatment with both, IND (10 mg/kg b.w.), or vehicle resulted in a reduction in glucagon-induced HGP due to a decrease in hepatic glycogen content. A complete depletion of the hepatic glycogen pool and thus a lack in glucagon-stimulated HGP was observed when IND was given intraperitoneally. These results indicate that the changes in HGP observed after pretreatment with IND may largely if not completely be due to a non-specific depletion in hepatic glycogen content and that IND does not exert a direct influence on HGP.

Blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients: prediction by computer modeling.

To establish a qualitative and quantitative model of blood glucose response to stress hormone exposure, healthy subjects (HS) on and off somatostatin (250 micrograms/h) as well as insulin dependent diabetic patients were infused with either epinephrine (E), glucagon (G), cortisol (F), growth hormone (GH) or with a cocktail of these hormones raising plasma stress hormones to values seen in severe diabetic ketoacidosis. The developed input/output model consists of two submodels interconnected in series plus two additional submodels for correction of gains describing both sensitivity of tissue response and utilisation as well as provision of glucose. It was shown and confirmed experimentally that blood glucose response to stress hormones was essentially nonlinear. Furthermore, the mathematical models for healthy subjects and for insulin dependent diabetic patients proved to be of the same structure and differed only in the values of some typical parameters. The model raises the possibility to describe and in part to predict blood glucose response to stress hormone exposure in healthy man and insulin dependent diabetic patients.

[Pathophysiology and therapy of diabetic ketoacidosis and of non-ketoacidotic hyperosmolar diabetic coma]. / Pathophysiológie und Therapie der diabetischen Ketoazidose und des nicht-ketoazidotischen hyperosmolaren Coma diabeticum.

Metabolic derangements in diabetic coma are the sequelae of insulin deficiency. These defects are aggravated by the actions of insulin counteracting ("diabetogenic") hormones and hypertonic dehydration, which both impair insulin action. Conversely, it has been shown that hypo-osmolar rehydration of a hyperosmolar, severely hyperglycaemic diabetic patient reduces insulin resistance and restores biological responsiveness of previously dehydrated insulin-dependent tissues towards insulin. Thus treatment of diabetic coma requires appropriate fluid and electrolyte replacement as a life-saving emergency action alongside insulin replacement. The use of proper rehydration during the past decade might also explain the reported fall in the insulin requirement for the treatment of diabetic coma from approximately 1,000 units per coma to low-dose insulin therapy. In order to guarantee proper treatment of severe hyperglycaemia and normalization of the hyperosmolar state, we feel that hypo-osmolar rehydration has to be initiated in parallel with low-dose insulin therapy (5 to 6 U/h) to restore the physiological response of the respective target tissues to insulin action and to ameliorate glucose utilization. This approach probably avoids a too rapid fall in plasma osmolarity, minimizes the risk of cerebral oedema and hypokalaemia, and improves survival. The development of severe diabetic ketoacidosis or of hyperosmolar non-ketotic diabetic coma should be prevented by advice to patients on the importance of metabolic monitoring, which can be done by proper self-monitoring of blood glucose. In addition, information should be provided on the detrimental metabolic effects of both dehydration and stress.

Reduction of postprandial blood glucose by the alpha-glucosidase inhibitor Miglitol (BAY m 1099) in type II diabetes.

The dose-dependency of the effects of the alpha-glucosidase inhibitor Miglitol (Bay m 1099) was investigated in 8 Type II diabetic patients. Administration of increasing doses of Miglitol once daily in the morning on four consecutive days concomitantly with a standardized meal containing 50 g starch led to a dose-dependent reduction in the maximal increase in the postprandial blood glucose level and in postprandial incremental AUC of blood glucose. The latter was significant for 50, 100, 75 and 200 mg Miglitol. Bay m 1099 also markedly retarded the appearance of the peak postprandial blood glucose concentration, which indicates delayed carbohydrate absorption. Serum insulin levels, documented as incremental AUCs of the serum insulin excursions, were not reduced dose dependently, because of the impaired insulin secretory capacity of the patients.

Effect of hyperosmolality on basal and hormone-stimulated hepatic glucose metabolism in vitro.

To understand better impairment of glucose utilization in diabetics during a hyperosmolal state, in vitro models were established to evaluate the effects of hyperosmolality on basal glucose uptake as well as glucagon dependent glucose release by isolated hepatocytes. In these studies simulating a hyperglycaemic (40 mmol glucose) and hyperosmolal (up to 500 mosm kg-1, NaCl as added solute) state basal hepatic glucose uptake was reversibly suppressed by 19% when osmolality was increased by as little as 10 mosm kg-1. No such effects on glucose uptake by isolated hepatocytes could be attained when the incubation's fluid osmolality was augmented by the addition of urea or mannitol. Estimations of the transport rates of 3-O-methylglucose and uptake of 2-deoxyglucose at 400 vs. 300 mosm kg-1 revealed that impaired intracellular enzymatic activity but not the transport rate of glucose into the cell were responsible for the hyperosmolal defect as uptake was more reduced (P less than 0.025) by increased osmolality for 2-deoxyglucose (16%) than for 3-O-methylglucose (13%). Glucagon dependent glucose release from isolated hepatocytes was diminished by 17.8% when the osmolality was raised to 400 mosm kg-1 by NaCl as added solute. These data obtained in vitro support the clinical contention that a hyperosmolal state, which corresponds to a loss of fluid in excess of solutes, is able to impair basal hepatic glucose uptake as well as glycogenolytic glucagon action on the liver.