Fall In Glucose Research Articles

The effects of hormone replacement therapy combined with vitamins C and E on antioxidants levels and lipid profiles in postmenopausal women with Type 2 diabetes

Background: Recent studies have demonstrated that oxidative modification of low-density lipoprotein (LDL) involving the formation of lipid peroxides (MDA), exerts several biological effects that may contribute to the onset and progression of cardiovascular diseases in postmenopausal women with Type 2 diabetes (DPMW). Therefore, the aim of our study was to evaluate the effect of hormone replacement therapy (HRT), vitamin C and E (VCE) treatments on lipid profiles, glucose and MDA levels as well as antioxidant vitamins and enzymes in plasma and red blood cells (RBC) in diabetic or non-diabetic postmenopausal women (PMW). Methods: Oral HRT and VCE supplementation for 6 weeks were compared with HRT treatment in 40 non-diabetic PMW and 40 DPMW. Results: In the 40 postmenopausal women (PMW) and 20 postmenopausal women with DPMW who received oral HRT and 20 DPMW who received HRT plus VCE, there was a significant fall in MDA, total cholesterol, LDL-cholesterol and triglyceride values. Glycated haemoglobin (HbA1c) in the DPMW was significantly improved with oral HRT and VCE although no significant change in white blood cell counts, vitamin A and HDL values occurred. Additionally, a fall in plasma glucose, HbA1c and platelet values also occurred in the PMW and DPMW groups by oral HRT and VCE treatments. There was a significant increase in plasma vitamin E and beta-carotene concentrations, catalase, glutathione peroxidase and reduced glutathione levels in RBC and plasma in DPMW by treatments with HRT and/or VCE. Conclusions: Daily VCE and HRT administrations both in PMW and DPMW seem to produce significant improvement in antioxidants concentrations, and the metabolic control of lipids and glucose. The HRT and VCE supplementations may strengthen the antioxidant defense system due to reducing blood glucose and lipid metabolites, and they may play a role in preventing cardiovascular diseases in postmenopausal women with Type 2 diabetes.

Pregnancy impairs the counterregulatory response to insulin-induced hypoglycemia in the dog.

The impact of pregnancy on the counterregulatory response to insulin-induced hypoglycemia was examined in six nonpregnant (NP) and six pregnant (P; 3rd trimester) conscious dogs by tracer and arteriovenous difference techniques. After basal sampling, insulin was infused intraportally at 30 pmol.kg(-1).min(-1) for 180 min. Insulin rose from 70 +/- 15 to 1,586 +/- 221 pmol/l and 27 +/- 4 to 1,247 +/- 61 pmol/l in the 3rd h in NP and P, respectively. Arterial glucose fell from 5.9 +/- 0.2 to 2.3 +/- 0.2 mmol/l in P. Glucose was infused in NP to equate the rate of fall of glucose and the steady-state concentrations in the groups (5.9 +/- 0.2 to 2.3 +/- 0.1 mmol/l in NP). Glucagon was 32 +/- 6, 69 +/- 11, and 48 +/- 10 ng/l (basal and 1st and 3rd h) in NP, but the response was attenuated in P (34 +/- 5, 46 +/- 6, 41 +/- 9 ng/l). Cortisol and epinephrine rose similarly in both groups, but norepinephrine rose more in NP (Delta3.01 +/- 0.46 and Delta1.31 +/- 0.13 nmol/l, P < 0.05). Net hepatic glucose output (NHGO; micromol.kg(-1).min(-1)) increased from 10.6 +/- 1.8 to 21.2 +/- 3.3 in NP (3rd h) but did not increase in P (15.1 +/- 1.5 to 15.3 +/- 2.8 micromol.kg(-1).min(-1), P < 0.05 between groups). The glycogenolytic contribution to NHGO in NP increased from 5.8 +/- 0.7 to 10.4 +/- 2.5 micromol.kg(-1).min(-1) by 90 min but steadily declined in P. The increase in glycerol levels and the gluconeogenic contribution to NHGO were 50% less in P than in NP, but ketogenesis did not differ. The glucagon and norepinephrine responses to insulin-induced hypoglycemia are blunted in late pregnancy in the dog, impacting on the magnitude of the metabolic responses to the fall in glucose.

Hepatic glucose autoregulation: responses to small, non-insulin-induced changes in arterial glucose.

The purpose of this study was to determine whether the sedentary dog is able to autoregulate glucose production (R(a)) in response to non-insulin-induced changes (<20 mg/dl) in arterial glucose. Dogs had catheters implanted >16 days before study. Protocols consisted of basal (-30 to 0 min) and bilateral renal arterial phloridzin infusion (0-180 min) periods. Somatostatin was infused, and glucagon and insulin were replaced to basal levels. In one protocol (Phl +/- Glc), glucose was allowed to fall from t = 0-90 min. This was followed by a period when glucose was infused to restore euglycemia (90-150 min) and a period when glucose was allowed to fall again (150-180 min). In a second protocol (EC), glucose was infused to compensate for the renal glucose loss due to phloridzin and maintain euglycemia from t = 0-180 min. Arterial insulin, glucagon, cortisol, and catecholamines remained at basal in both protocols. In Phl +/- Glc, glucose fell by approximately 20 mg/dl by t = 90 min with phloridzin infusion. R(a) did not change from basal in Phl +/- Glc despite the fall in glucose for the first 90 min. R(a) was significantly suppressed with restoration of euglycemia from t = 90-150 min (P < 0.05) and returned to basal when glucose was allowed to fall from t = 150-180 min. R(a) did not change from basal in EC. In conclusion, the liver autoregulates R(a) in response to small changes in glucose independently of changes in pancreatic hormones at rest. However, the liver of the resting dog is more sensitive to a small increment, rather than decrement, in arterial glucose.

Insulin resistance and clomiphene resistance—Is there any correlation?

Objective: There is a recent trend to use insulin sensitizers in women with Polycystic Ovarian syndrome (PCOS). A debate is on as to which subset of women with PCOS benefit with this therapy. Our aim of the study was to evaluate the insulin sensitivity in PCOS women who ovulate (responders) and do not ovulate ( nonresponders) with clomiphene citrate and also normal ovulatory non PCOS women. Design The PCOS women who did not ovulate with maximum dose of clomiphene citrate (200mg/ day) were selected for the study. Their insulin status was evaluated by fasting insulin levels, fasting glucose to insulin ratio and insulin sensitivity by short insulin tolerance test. They were compared with insulin status of PCOS women who responded to clomiphene citrate 100 or 150mg/day dose schedule. The comparison was also done with the insulin status of normal ovulatory women with infertility. Material & methods This prospective study was conducted in Reproductive medicine Unit of Christian medical College with approval of the institutional review board. Sixty clomiphene resistant women with PCOS (group I) were selected for the trial. 23 responders (group II) and 21 normally ovulatory women (group III) were also evaluated. Their body mass indexes, waist to hip ratio were recorded. The fasting blood was taken for glucose and insulin levels. Insulin sensitivity was measured using the short insulin tolerance test. In brief an intravenous bolus injection of actrapid insulin (0.05 U/kg) was given. Blood samples were drawn from the contra lateral arm at 5 min before and at 3, 5, 7,9,12 and 15 min after insulin injection. Glucose was then injected i.v. at 15 min to prevent a fall in plasma glucose level. The rate of fall of blood glucose was calculated from the linear regression of all values between 3 min and 15 min; this rate of fall was taken as the index of insulin sensitivity. Results. ( Table I) Tabled 1 The body mass index and waist to hip ratio were comparable in all 3 groups. The fasting insulin was significantly higher in nonresponders as compared to responders and ovulatory women. The multivariate analysis showed that fasting insulin was significantly higher in nonresponders even after adjusting for BMI. There was trend towards lower glucose- insulin ratio in nonresponders, though this was not statistically significant. Glucose-insulin ratio of < 4.5 is considered as index of insulin resistance. 28.3% women of group I, 4.3% of group II and none in group III had glucose- insulin ratio < 4.5. There was trend towards higher insulin resistance in nonresponders as evaluated by the insulin sensitivity. Conclusions The clomiphene resistant PCOS women are more insulin resistant than clomiphene responder PCOS. The insulin sensitivity seems to be similar in clomiphene responder PCOS and normally ovulatory non PCOS women. Therefore clomiphene resistant PCOS women should benefit with insulin sensitizers.

Effects of an Oral Glucose Challenge on Metabolic and Hormonal Responses to Exercise in Active Prepubertal Girls

To examine hormonal and metabolic effects of an oral challenge in glucose (≈ 16 g), 15 prepubertal girls performed a 30-min ergocycle test at 60% of Wmax. Among them, 8 ingested an oral glucose challenge between 2 and 3 min after the beginning of the exercise whereas the other 7 girls received no fluid intake. Plasma glucose is influenced by the oral challenge, as the values obtained at the 15th and 30th min are higher than those of the control group. Plasma FFA, catecholamines, and insulin are not significantly modified by the oral challenge. Therefore, it seems that a challenge in glucose at the beginning of a prolonged exercise could avoid a fall in plasma glucose.

Cancer Cachexia and Tumor Growth Reduction in Walker 256 Tumor-Bearing Rats Supplemented With N-3 Polyunsaturated Fatty Acids for One Generation

In this study we investigated the effect of lifelong supplementation of the diet with coconut oil (CO, rich in saturated fatty acids) or fish oil (FO, rich in n-3 polyunsaturated fatty acids, PUFAs) on tumor growth, animal survival, and metabolic indicators of cachexia in adult rats. Female Wistar rats were supplemented with CO or FO prior to mating and then throughout pregnancy and gestation, and then the male offspring were supplemented from weaning until 90 days of age. Then they were inoculated subcutaneously with Walker 256 tumor cells. Tumor weight at 14 days in control rats (those fed standard chow) was approximately 20 g. These animals displayed cancer cachexia, which was characterized by loss of weight, hypoglycemia, hyperlacticidemia, hypertriacylglycerolemia, and depletion of glycogen stores. Supplementation of the diet with CO did not change these parameters, except that there was a smaller decrease in serum triacylglycerol concentration. Supplementation of the diet with FO significantly decreased tumor growth (by approximately 60%), increased survival (50% at 30 days postinoculation vs. 30% in the controls and 13.5% in the CO group), and prevented the fall in body weight. Furthermore, FO supplementation partly abolished the fall in serum glucose, totally prevented the elevation in serum lactate concentrations, partly prevented the hypertriacylgylcerolemia, and preserved tissue glycogen stores. Lifelong consumption of FO, rich in n-3 PUFAs, protects against tumor growth and cancer cachexia and improves survival.

Defective activation of skeletal muscle and adipose tissue lipolysis in type 1 diabetes mellitus during hypoglycemia.

The increased risk of hypoglycemia during intensified treatment of type 1 diabetes mellitus (T1DM) patients, who have a deficient glucagon secretory response, is largely attributed to the development of suppressed adrenomedullary responses. A consequence of this impairment of catecholamine secretion might be reduced lipolysis in major target tissues (muscle and adipose) and, in turn, increased glucose metabolism. To test this hypothesis, we used microdialysis to monitor glycerol (index of lipolysis) in the extracellular fluid of skeletal muscle and adipose tissue and assessed whole-body glucose use by measuring [6,6-(2)H(2)]glucose enrichment in plasma in seven intensively treated T1DM patients and eight nondiabetic subjects who received a 3-h insulin infusion (0.8 mU/kg.min) on two occasions: during mild-moderate hypoglycemia or euglycemia. In the hypoglycemic study, the rise in plasma epinephrine was approximately 50% less in the T1DM patients despite a greater fall in plasma glucose (to 3.0 vs. 3.5 mM in controls; P < 0.05). Moreover, the rate of glucose flux and the plasma-extracellular fluid glucose gradient in muscle was increased during hypoglycemia in T1DM subjects compared with controls. Glycerol levels in muscle, adipose, and plasma fell similarly in both groups in the first hour. Thereafter, tissue glycerol remained suppressed in the T1DM patients but rebounded significantly (P < 0.01) in the control subjects. The glycerol response in muscle and adipose tissue was significantly correlated with plasma epinephrine concentration (r = 0.73, P = 0.002; and r = 0.52, P = 0.04, respectively), and inversely correlated with whole-body glucose disposal (r = -0.51, P = 0.05; and r = -0.50, P = 0.05). To determine whether the absence of the lipolytic response is limited to deficient catecholamine release, we perfused muscle and adipose tissue in situ with the selective beta(2)-agonist terbutaline during hyperinsulinemic euglycemia. Local addition of agonist increased glycerol and blood flow in both muscle and adipose (P < 0.01 and P < 0.05, respectively) similarly in T1DM and control subjects. We conclude that deficient release of (rather than impaired responsiveness to) catecholamines in T1DM prevents the local fat breakdown within muscle and adipose tissue that normally occurs during mild-moderate hypoglycemia. This defect within peripheral tissues may lead to a delayed increase in glucose disposal that could contribute to the severity of hypoglycemia when it is prolonged.

Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles.

To determine whether, in the presence of constant insulin concentrations, a change in glucose concentrations results in a reciprocal change in endogenous glucose production (EGP), glucagon ( approximately 130 ng/l) and insulin ( approximately 65 pmol/l) were maintained at constant "basal" concentrations while glucose was clamped at approximately 5.3 mM (euglycemia), approximately 7.0 mM (sustained hyperglycemia; n = 10), or varied to create a "postprandial" profile (profile; n = 11). EGP fell slowly over the 6 h of the euglycemia study. In contrast, an increase in glucose to 7.13 +/- 0.3 mmol/l resulted in prompt and sustained suppression of EGP to 9.65 +/- 1.21 micromol x kg-1 x min-1. On the profile study day, glucose increased to a peak of 11.2 +/- 0.5 mmol/l, and EGP decreased to a nadir of 6.79 +/- 2.54 micromol x kg-1 x min-1 by 60 min. Thereafter, the fall in glucose was accompanied by a reciprocal rise in EGP to rates that did not differ from those observed on the euglycemic study day (11.31 +/- 2.45 vs. 12.11 +/- 3.21 micromol x kg-1 x min-1). Although the pattern of change of glucose differed markedly on the sustained hyperglycemia and profile study days, by design the area above basal did not. This resulted in equivalent suppression of EGP below basal (-1,952 +/- 204 vs. -1,922 +/- 246 mmol. kg-1. 6 h-1). These data demonstrate that, in the presence of a constant basal insulin concentration, changes in glucose within the physiological range rapidly and reciprocally regulate EGP.

Subcutaneous glucose sensor values closely parallel blood glucose during insulin-induced hypoglycaemia.

To assess the accuracy of the Minimed continuous glucose monitoring system (CGMS) in estimating blood glucose concentration during a controlled reduction in blood glucose. We studied nine adolescent diabetics (age 14 +/- 1.5 years) wearing the CGMS during hyperinsulinaemic hypoglycaemic clamp studies. The glucose values obtained by the CGMS were compared with the venous blood samples taken during the studies and measured at the bedside using a glucose oxidase technique. Blood glucose was lowered from euglycaemia to a mean of 2.8 mmol/l over 120 min and maintained at that level for a further 40 min. A total of 429 paired glucose measurements were available for analysis. Analysis using weighted Deming regression and t-tests revealed small differences between the methods, with blood glucose levels slightly higher than interstitial fluid levels. The mean difference across all values was 0.13 mmol/l. The observed difference was greatest at blood glucose values < 3.3 mmol/l. This study suggests that during a fall in systemic glucose the subcutaneous glucose sensor provides an accurate reflection of blood glucose. However, a small difference is apparent at blood glucose values < 3.3 mmol/l.

Hypoglycaemic and hypolipidemic effect of ethanolic extract of seeds of Eugenia jambolana in alloxan-induced diabetic rabbits

The hypoglycaemic and hypolipidemic effect of ethanolic extract obtained from seeds of E. jambolana was investigated in alloxan-induced diabetic rabbits. Hypoglycaemic activity was assessed by reduction in fasting blood glucose (FBG) at 90 min and also fall in peak blood glucose during glucose tolerance test (GTT) in sub-diabetic and mild diabetic (MD) rabbits, but in severe diabetic (SD) rabbits by reduction in FBG at 90 min. Ethanolic extract (100 mg/kg body weight) when given orally to sub-diabetic (AR) for 1 day, MD for 7 days and SD for 15 days showed significant fall in FBG at 90 min (12% AR, 18.9% MD and 29% SD) and also produced 16.9% fall in peak blood glucose in AR and 21% in MD rabbits during GTT. When administered daily for 15 days to MD and SD rabbits, significant fall in FBG (41.3% MD, 31.6% SD) and glycosylated haemoglobin (GHb) levels (23.3% MD, 26.6% SD) were observed, while serum insulin level showed significant increase (32.8% MD, 26.9% SD). Liver and muscle glycogen content also increased. The ethanolic extract of seeds also exhibited significant hypolipidemic effect as evident from fall in total serum cholesterol (TC)/high density lipoprotein cholesterol (HDL-c) ratio, serum low density lipoprotein cholesterol (LDL-c) levels and decreased activity of HMG-CoA reductase. The histopathological studies of liver, pancreas and aorta in alcoholic extract treated diabetic groups revealed almost normal appearance.

Oral arginine has no acute effect on blood glucose concentrations or glucose production in type 2 diabetic volunteers

A 49-year old male with type 2 diabetes mellitus was given 3 grams (gm) of oral arginine per hour for 10-hours, the effects on plasma glucose, insulin, C-peptide and glucose concentrations were determined. Oral arginine administration decreased plasma glucose concentrations and glucose production by approximately 40% over an 8-hr study (5%/hr). Supplemental arginine is inexpensive and may provide physicians with an additional tool in the treatment of type 2 diabetes. Six obese volunteers with type 2 diabetes were studied to document the effects of oral arginine on fasting glucose concentration and glucose production rate (GPR). Patients were admitted to the General Clinical Research Center for a 3-day stay. Oral arginine was ingested at 3-gm per hour starting at 4 am until 2 pm on day 2 or day 3 (randomized to arginine or to no-arginine supplement). Oral arginine administration was well tolerated and failed to increase C-peptide or insulin concentrations over the 10-hr period of administration. Unlike what was documented in the first diabetic patient, the prospective administration of oral arginine failed to reduce glucose concentrations (9.9 ± 1.8 vs 10.3 ± 1.8 mM) or GPR (14.7 ± 1.5 vs 15.7 ± 2.3 μmol/kg/min; arginine vs no-arginine; NS). The fall in blood glucose over the 8-hour period was not significantly increased during oral arginine administration (3.3% vs 2.6% per hour, arginine vs no-arginine, NS). These data demonstrate that 3-gm per hour of oral arginine had no effect on GPR or fasting blood glucose concentration in obese type 2 diabetic volunteers.

Effects of inhibition of ATP-sensitive potassium channels on metabolic vasodilation in the human forearm

Experimental data suggest that vascular ATP-sensitive potassium (KATP) channels may be an important determinant of functional hyperaemia, but the contribution of KATP channels to exercise-induced hyperaemia in humans is unknown. Forearm blood flow was assessed in 39 healthy subjects (23 males/16 females; age 22±4 years) using the technique of venous occlusion plethysmography. Resting forearm blood flow and functional hyperaemic blood flow (FHBF) were measured before and after brachial artery infusion of the KATP channel inhibitors glibenclamide (at two different doses: 15 and 100µg/min) and gliclazide (at 300µg/min). FHBF was induced by 2min of non-ischaemic wrist flexion–extension exercise at 45 cycles/min. Compared with vehicle (isotonic saline), glibenclamide at either 15µg/min or 100µg/min did not significantly alter resting forearm blood flow or peak FHBF. The blood volume repaid at 1 and 5min after exercise was not diminished by glibenclamide. Serum glucose was unchanged after glibenclamide, but plasma insulin rose by 36% (from 7.2±0.8 to 9.8±1.3m-units/l; P = 0.02) and 150% (from 9.1±1.3 to 22.9±3.5m-units/l; P = 0.002) after the 15 and 100µg/min infusions respectively. Gliclazide also did not affect resting forearm blood flow, peak FHBF, or the blood volume repaid at 1 and 5min after exercise, compared with vehicle (isotonic glucose). Gliclazide induced a 12% fall in serum glucose (P = 0.009) and a 38% increase in plasma insulin (P = 0.001). Thus inhibition of vascular KATP channels with glibenclamide or gliclazide does not appear to affect resting forearm blood flow or FHBF in healthy humans. These findings suggest that vascular KATP channels may not play an important role in regulating basal vascular tone or skeletal muscle metabolic vasodilation in the forearm of healthy human subjects.

Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state.

The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well. In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.

Sex steroid biosynthesis in white adipose tissue.

White adipose tissue has long been considered a mere storage site for lipids and therefore an energetic reservoir for the maintenance of vital cell functions. When a fall in glucose occurs, lipolysis leads to the release of fatty acids for use by a variety of tissues such as muscle, liver and kidney. Partial oxidation of fatty acids also generates ketones, which serve as an alternate fuel source for the brain and other tissues. Conversely, an increase in glucose and lipids results in increased adipose fatty acid transport and lipogenesis. Fat metabolism depends on energy requirements and is regulated by nutrient, neural and hormonal signals [1].

Effects of the imidazoline ligands efaroxan and KU14R on blood glucose homeostasis in the mouse

The putative imidazoline I 3 receptor antagonist 2-(2-ethyl-2,3-dihydrobenzo[ b]furan-2-yl)-1 H-imidazole (KU14R) has been shown to block the effects of the atypical I 3 agonist efaroxan at the level of the ATP-sensitive K + (K ATP) channel in isolated pancreatic islet β cells, but its effects in vivo are not known. We have therefore investigated the effects of KU14R on blood glucose and insulin level in vivo. When KU14R was administered before or after a hypoglycaemic dose of efaroxan, the fall in blood glucose was at least additive. When the antihyperglycaemic imidazoline ligand S22068 was administered after a dose of KU14R, it did not alter the hypoglycaemic response. In the mouse isolated vas deferens preparation, neither rauwolscine (at concentrations which competitively antagonised the inhibitory response to 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK14304)) nor KU14R affected inhibition produced by S22068. At 10 −4 M, KU14R had weak α 2-adrenoceptor antagonist activity. We conclude that KU14R does not act as an antagonist of either efaroxan or S22068 at an imidazoline site in vivo.

Insulin sensitively controls the glucagon response to mild hypoglycemia in the dog.

In the present study, we examined how the arterial insulin level alters the alpha-cell response to a fall in plasma glucose in the conscious overnight fasted dog. Each study consisted of an equilibration (-140 to -40 min), a control (-40 to 0 min), and a test period (0 to 180 min), during which BAY R 3401 (10 mg/kg), a glycogen phosphorylase inhibitor, was administered orally to decrease glucose output in each of four groups (n = 5). In group 1, saline was infused. In group 2, insulin was infused peripherally (3.6 pmol. kg(- 1). min(-1)), and the arterial plasma glucose level was clamped to the level seen in group 1. In group 3, saline was infused, and euglycemia was maintained. In group 4, insulin (3.6 pmol. kg(-1). min(-1)) was given, and euglycemia was maintained by glucose infusion. In group 1, drug administration decreased the arterial plasma glucose level (mmol/l) from 5.8 +/- 0.2 (basal) to 5.2 +/- 0.3 and 4.4 +/- 0.3 by 30 and 90 min, respectively (P < 0.01). Arterial plasma insulin levels (pmol/l) and the hepatic portal-arterial difference in plasma insulin (pmol/l) decreased (P < 0.01) from 78 +/- 18 and 90 +/- 24 to 24 +/- 6 and 12 +/- 6 over the first 30 min of the test period. The arterial glucagon levels (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) rose from 43 +/- 5 and 5 +/- 2 to 51 +/- 5 and 10 +/- 5 by 30 min (P < 0.05) and to 79 +/- 16 and 31 +/- 15 (P < 0.05) by 90 min, respectively. In group 2, in response to insulin infusion, arterial insulin (pmol/l) was elevated from 48 +/- 6 to 132 +/- 6 to an average of 156 +/- 6. The hepatic portal-arterial difference in plasma insulin was eliminated, indicating a complete inhibition of endogenous insulin release. The arterial glucagon level (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) did not rise significantly (40 +/- 5 and 7 +/- 4 at basal, 44 +/- 4 and 9 +/- 4 at 90 min, and 44 +/- 8 and 15 +/- 7 at 180 min). In group 3, when euglycemia was maintained, the insulin and glucagon levels and the hepatic portal-arterial difference remained constant. In group 4, the arterial plasma glucose level remained basal (5.9 +/- 1.1 mmol/l) throughout, whereas insulin infusion increased the arterial insulin level to an average of 138 +/- 6 pmol/l. The hepatic portal-arterial difference in plasma insulin was again eliminated. Arterial glucagon level (ng/l) and the hepatic portal-arterial difference in plasma glucagon (ng/l) did not change significantly (43 +/- 2 and 9 +/- 2 at basal, 39 +/- 3 and 9 +/- 2 at 90 min, and 37 +/- 3 and 7 +/- 2 at 180 min). Thus, a difference of approximately 120 pmol/l in arterial insulin completely abolished the response of the alpha-cell to mild hypoglycemia.

Reversal of diabetic retinopathy in streptozotocin induced diabetic rats using traditional Indian anti-diabetic plant,Azadirachta indica (L.).

This study was carried out to investigate the effect of oral feeding of water extract of fresh leaves ofAzadirachta indica (Fam:Meliaceae) in streptozotocin induced diabetes and its associated retinopathy in rats. Treatment of the diabetic rats with aqueous extract of leaves ofA. indica at a dose of 250 mg/kg body weight for 16 weeks resulted in gradual but significant fall in blood glucose and improvement in serum total, LDL and HDL cholesterol and triacylglycerol which increased in diabetic rats. It also showed improvement in body weight and reversed retinopathy.

Prevention of overt hypoglycemia during exercise: stimulation of endogenous glucose production independent of hepatic catecholamine action and changes in pancreatic hormone concentration.

These studies were conducted to determine the magnitude and mechanism of compensation for impaired glucagon and insulin responses to exercise. For this purpose, dogs underwent surgery >16 days before experiments, at which time flow probes were implanted and silastic catheters were inserted. During experiments, glucagon and insulin were fixed at basal levels during rest and exercise using a pancreatic clamp with glucose clamped (PC/GC; n = 5), a pancreatic clamp with glucose unclamped (PC; n = 7), or a pancreatic clamp with glucose unclamped + intraportal propranolol and phentolamine hepatic alpha- and beta-adrenergic receptor blockade (PC/HAB; n = 6). Glucose production (R(a)) was measured isotopically. Plasma glucose was constant in PC/GC, but fell from basal to exercise in PC and PC/HAB. R(a) was unchanged with exercise in PC/GC, but was slightly increased during exercise in PC and PC/HAB. Despite minimal increases in epinephrine in PC/GC, epinephrine increased approximately sixfold in PC and PC/HAB during exercise. In summary, during moderate exercise, 1) the increase in R(a) is absent in PC/GC; 2) only a moderate fall in arterial glucose occurs in PC, due to a compensatory increase in R(a); and 3) the increase in R(a) is preserved in PC/HAB. In conclusion, stimulation of R(a) by a mechanism independent of pancreatic hormones and hepatic adrenergic stimulation is a primary defense against overt hypoglycemia.

The effect of maternal undernutrition on ovine fetal growth.

Modifications in maternal nutrition during pregnancy can significantly disrupt fetal growth and subsequent post-natal health and survival. This study investigated the effects of undernutrition on fetal growth and the potential mechanisms involved. Tissue from pregnant ewes (n=27) was investigated on days 45, 90 and 135 of gestation (term = approximately 150 days). The thoracic girth (P<0.05) was greater in fetuses from nutrient restricted ewes on day 45 and there was also a trend towards an increased gut weight (P<0.08). By day 90, the fetal brain and thymus weight were lighter in underfed than in well-fed animals whilst the weight of the fetal ovaries was heavier (P<0.05). On day 135 the fetal heart, pancreas, thymus, gut and kidney weights were lighter in undernourished ewes (P<0.05). When expressed as a percentage of fetal body weight, significance was retained in the heart, pancreas and thymus (P<0.05). Bone growth was also affected. At day 90 the fetal femur and metatarsal were longer in underfed mothers (P<0.05). In contrast, the fetal humerus and scapula were shorter in underfed than in well-fed animals on day 135 (P<0.05) when the weight of the semitendinosus muscle (P<0.05) was also reduced. The fall in fetal glucose (P<0.1), insulin (P<0.01) and IGF-I (P<0.01) levels in underfed ewes on day 135 may have compromised fetal growth. Fetal plasma IGF binding protein-2 also increased between days 90 and 135 in underfed ewes (P<0.03), whilst levels were unaltered in well-fed animals. Although maternal and fetal plasma IGF-I levels increased with gestation (P<0.01) and the placentome morphology altered in all ewes (P<0.05), the fall in placental mass (P<0.05), amniotic and allantoic glucose concentrations (P<0.05) and maternal plasma glucose and insulin levels (P<0.05) in underfed ewes in late gestation may have compromised fetal substrate delivery. These perturbations in fetal development may have significant implications on adult health and carcass conformation, raising important health and economic issues in medical and agricultural sectors.

Purification, Characterization, and Biological Activity of Insulins from the Spotted Dogfish, Scyliorhinus canicula, and the Hammerhead Shark, Sphyrna lewini

Insulin was purified from pancreatic extracts of two elasmobranch species belonging to different families in the order Carcharhiniformes, the European spotted dogfish, Scyliorhinus canicula (Scyliorhinidae), and the hammerhead shark, Sphyrna lewini (Carcharhinidae). The amino acid sequence of dogfish insulin was established as A-chain GIVDHCCRNT10CSLYDLEGYC20NQ and B-chain LPSQHLCGSH10LVETLYFVCG20QKGFYYVPKV30. The primary structure of hammerhead shark insulin was similar to that of dogfish insulin with only 2 amino acid substitutions at A8 (R → H) and B30 (V → I). The elasmobranch insulins were markedly different from human insulin (17 amino acid substitutions) but all the residues in human insulin that are believed to be important in determining the receptor binding conformation (B6, B8, B11, B13, B23, B24, B25, A2, A3, and A19) have been conserved in the elasmobranch insulins with the exception of the conservative substitution Phe → Tyr at B25. Consistent with this, dogfish and human insulin showed almost identical binding affinity to the recombinant solubilized human insulin receptor (KD values of 14.0 and 18.6 pM, respectively; relative potency 133%). Previous studies have shown that bovine insulin produces severe and sustained hypoglycemia in elasmobranchs but the effect is of slow onset. Bolus arterial injections of dogfish insulin (10 nmol·kg−1) into unanesthetized, fasting dogfish (n = 9) produced no changes in blood glucose, 3-hydroxybutyrate, and acetoacetate concentrations over a 4-h period. In a second series of experiments (n = 7), dogfish insulin (10 nmol·kg−1) produced a significant (P < 0.05) fall in blood glucose after 12 h that persisted for at least 48 h, but no change in ketone body concentrations. The data indicate that the metabolic actions of an endogenous elasmobranch insulin in an elasmobranch are similar to those previously described for mammalian insulin.