Effect of chronic sulfonylurea treatment on the myocardium of insulin-dependent diabetic rats

Adult rats treated with high doses of streptozocin became progressively more hyperglycemic during the first month of the diabetic condition. Treatment of these rats with the sulfonylurea glyburide halted, and in some cases, reversed this process in a high percentage of the diabetics. Associated with the glyburide-mediated improvement in fasting blood glucose levels was an increase in myocardial glucose utilization and lactate production. The stimulation of myocardial glucose utilization by insulin was greater in glyburide-treated hearts, indicating that the hyperglycemic agent increased insulin responsiveness. The sulfonylurea also partially restored insulin sensitivity to the normal range. In agreement with previous studies, myocardial mechanical function was significantly impaired in the diabetic heart. When treated with glyburide, the severity of the mechanical defect was significantly less. The sulfonylurea also promoted an increase in myosin ATPase activity and a shift in the myosin isozyme pattern in favour of the most active V1 form. These results imply that glyburide therapy can provide benefit to the diabetic heart by improving energy metabolism and promoting a shift in myosin towards the most active form.     

The effect of insulin on the heart

Insulin infusion has been advocated in the treatment of myocardial ischaemia and myocardial infarction. There is evidence from experimental animal studies for a protective effect of high-dose insulin administration in myocardial ischaemia and myocardial infarction. In some relatively small study populations a reduction in mortality was reported in those patients who received glucose-insulin-potassium (GIK) during myocardial infarction, which was confirmed in two meta-analyses. However, it has not been possible to reproduce these positive results in large randomised clinical trials. (Neth Heart J 2010;18:255-9.)     

Systemic administration of HVJ viral coat-liposome complex containing human insulin vector decreases glucose level in diabetic mouse: A model of gene therapy

In this study, we examined the feasibility of a systemic administration of HVJ-liposome complex containing human insulin construct into the blood in mice via the tail vein. Transfection of human insulin vector resulted in a transient decrease in serum glucose in streptozotocin (SZT)-induced diabetic mice, accompanied by the detection of human insulin in the liver and spleen. In accordance with the decreased glucose, plasma immunoreactive insulin could be detected up to 14 days after a single transfection in mice transfected with insulin vector. Repeated intravenous injection of human insulin vector every week resulted in a sustained decrease in serum glucose over a 4-week period, accompanied by the detection of C-peptide fragments and a significant decrease in BUN and creatinine. Here, we demonstrated the feasibility of intravenous systemic administration of an insulin vector that results in a sustained improvement of diabetic glucose metabolism.     

Hypoglycémie spontanée et insuffisance rénale chronique.

Although glucose intolerance occurs as a consequence of chronic renal failure, improvement of a diabetic state by deterioration of renal function is a well known phenomenon. Recently occasional cases of spontaneous hypoglycemia in patients with chronic renal failure have been reported; two such cases and the results of metabolic studies are described in this paper. Pituitary, thyroid and adrenal function appeared to be normal. The results of an oral glucose tolerance test were normal; an appropriate insulin response was demonstrated in one patient, and a slightly elevated basal insulin value with a delayed insulin response to oral administration of glucose was demonstrated in the other. An insulin tolerance test did not support the hypothesis of increased insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concentration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concnetration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase in insulin values. The plasma alanine concentration was low and the proinsulin/insulin ratio was increased. The origin of this hypoglycemia is not clear but is probably multifactorial. However, low hepatic glycogen stores and inadequate gluconeogenesis due to substrate deficiency seem to be involved.     

Long-term continuous intraperitoneal insulin treatment in brittle diabetes.

Attempts to achieve a fair metabolic equilibrium in a young woman with brittle diabetes by continuous subcutaneous, intramuscular, and continuous intravenous administration of insulin were unsuccessful. Continuous intraperitoneal administration of insulin through a permanently inserted polyethylene catheter connected to an open-loop peristaltic pump led to an appreciable improvement in mean blood glucose concentration, mean amplitude of glycaemic excursions, and M value and to normalisation of intermediate metabolic products. The peritoneal catheter was well tolerated for over 120 days without appreciable adverse effects. This case suggests that long-term intraperitoneal administration of insulin is a feasible therapeutic approach in the management of brittle diabetes.     

Involvement of nitric oxide in insulin induced memory improvement

Although brain was considered as an insulin-insensitive organ, recently it has appeared that insulin has some interesting effects on some brain regions like hippocampus. It has been known that intra-hippocampally administered insulin can improve learning and memory. Knowing that insulin can stimulate nitric oxide (NO) synthesis via eNOS activation and also that NO synthase (NOS) inhibitors can affect learning and memory, the aim of this study was to assess if NO is involved in insulin induced memory improvement. Wistar male rats were intra-CA1 cannulated and the effect of post-training and pre-probe trial intra-hippocampal administration of N-nitro-l-arginine methyl ester (l-NAME) (5, 10, 30 μg), insulin + l-NAME ± l-arginine were assessed in a single-day testing version of Morris water maze (MWM) task. Our results show that, l-NAME can prevent insulin induced memory improvement. This drug had no effect on escape latency of a non-spatial visual discrimination task. Therefore, it seems that endogenous nitric oxide has a role in spatial learning and memory improvement caused by insulin.     

Improved cardiac function following hormonal therapy in brain dead pigs: relevance to organ donation

Deterioration of function in brain dead baboons is associated with depletion of both myocardial energy stores and certain circulating hormones, notably thyroxine, cortisol, and insulin. We have therefore investigated the effect of the administration of these three hormones to the brain dead pig; their value has been assessed on both the freshly excised and stored donor heart. Brain death was induced by ligation of the two arteries to the upper part of the body which arise from the aortic arch. Storage of selected hearts was by continuous hypothermic perfusion for 20 to 24 hr. Hearts were biopsied for estimation of adenosine triphosphate, creatine phosphate, lactate, and glycogen, and were subsequently functionally tested. Six groups of pigs were studied. Hearts were tested from control pigs which had not undergone brain death (A1), from brain dead pigs which had received intravenous fluid and inotropic support for 4 hr (B1), and from brain dead pigs which had in addition received 2 hr of hormonal therapy (thyroxine 2 micrograms cortisol 100 mg, and insulin 5-10 IU hourly) (C1). A further 3 groups (A2-C2) underwent management identical to A1-C1, but in addition the hearts were stored for 24 hr. Brain death in pigs was followed by a consumption of myocardial energy stores, despite anaerobic glycolysis; this was associated with reduced myocardial function. The administration of hormones to the brain dead pig led to some replenishment of myocardial energy and glycogen reserves and reduction in lactate, with associated improvement in hemodynamic function. A period of hypothermic perfusion storage appeared to reverse the anaerobic metabolism occurring in the heart in the nonhormonally treated brain dead animal, though not in the hormonally treated animal, and led to replenishment of glycogen reserves in nontreated animals. The observation that both better function and an increase in myocardial energy stores occurred in hormonally treated, stored hearts, even though perfusate lactate dehydrogenase rose to significantly higher levels during hypothermic perfusion storage, and tissue lactate levels remained high, suggests that thyroxine promotes both aerobic and anaerobic metabolism in brain dead animals.     

Short-term effects of growth hormone on myocardial glucose uptake in healthy humans

Cardiac muscle is characterized by insulin resistance in specific heart diseases such as coronary artery disease and congestive heart failure, but not in generalized disorders like diabetes mellitus and essential hypertension when cardiac manifestations are absent. To examine whether the insulin antagonistic effect of growth hormone (GH) acts upon the heart, we compared insulin-stimulated whole body and myocardial glucose uptake with and without GH administration during a 3.5-h euglycemic-hyperinsulinemic clamp in eight healthy males. Myocardial 2-deoxy-2-[(18)F]fluoro-D-glucose uptake was measured with positron emission tomography. The data were converted to myocardial glucose uptake by tracer kinetic analysis. GH did not change the rate-pressure product. GH decreased whole body insulin-stimulated glucose disposal by 26% (48.0 +/- 12.1 vs. control 62.8 +/- 6.1 micromol. kg(-1). min(-1), P < 0.02). Free fatty acids were suppressed to a similar extent with and without GH during the insulin clamp. Insulin-stimulated myocardial glucose uptake was similar in the presence and in the absence of GH (0.34 +/- 0.05 and 0.31 +/- 0.03 micromol. g(-1). min(-1), P = 0.18). In conclusion, GH does not impair insulin-stimulated myocardial glucose uptake despite a considerable whole body insulin antagonistic effect. Myocardial insulin resistance is not an inherent consequence of whole body insulin resistance.     

Insulin-mediated modifications of myocardial lipoprotein lipase and lipoprotein metabolism

Recirculating organ perfusion in vitro was conducted with hearts from control rats, animals given a single dose of streptozotocin (65 mg/kg) 48 h earlier, and streptozotocin-treated rats administered insulin (5 units), 2 h prior to organ perfusion. During 45-min perfusions, the lipolysis of very low density lipoprotein (VLDL) triglyceride was significantly less in hearts from diabetics than in controls (41.9 +/- 7.3% of control). This was associated with significant reductions in heparin-releasable (functional) lipoprotein lipase and tissue lipoprotein lipase of perfused hearts. The decreases in VLDL triglyceride metabolism and the levels of myocardial lipoprotein lipase were completely reversed by treatment of diabetic rats with insulin 2 h prior to study. Similar improvement of VLDL triglyceride metabolism and increases in myocardial lipoprotein lipase activity were observed in hearts from diabetic rats by direct addition of 100 milliunits/ml of insulin to the recirculating perfusion media. Under these conditions, the increase in both fractions of lipoprotein lipase in response to insulin was completely inhibited, and utilization of VLDL triglyceride was partially inhibited by pre-perfusion with cycloheximide for 10 min. The data derived from either VLDL triglyceride lipolysis in organ perfusion or direct measurement of myocardial lipoprotein lipase demonstrate a direct effect of insulin on myocardial lipoprotein lipase activity, and suggest that the response to insulin may be due in part to effects on protein synthesis.     

Effect of short- and long-term chlorpropamide therapy on oral glucose tolerance and erythrocyte insulin receptors in non-obese non-insulin dependent diabetes mellitus

Erythrocyte (RBC) insulin receptors and the insulin response to glucose load (oGTT) were evaluated in ten male, non-obese, non-insulin dependent diabetic patients (NIDDM) before and after 14 and 90 days of 250 mg/day of chlorpropamide administration. In addition, as a control group, twelve healthy non-obese subjects were studied. Diabetic patients with fasting plasma glucose level higher than 14 mmol/l (group A), presented a significant improvement in the incremental glucose area only after 90 days of therapy. There was an evident reduction in insulin secretion, in comparison to normals, which however increased progressively during drug administration. No alterations in insulin binding to RBC receptors were observed either before or after the use of chlorpropamide, but the normalization of the initially low number of receptors per cell (N) and an increased high affinity constant (Ke) were achieved. In group B with fasting glucose less than 14 mmol/l there was a significant reduction in plasma glucose levels during oGTT without changes in glucose areas and a significant improvement of the insulin secretion was noted only in the early samples. Except for transient alterations in N and Ke no significant changes were observed in insulin-RBC binding parameters. We conclude that the improvement in the glucose tolerance in NIDDM is associated both to a greater insulin secretion and to the correction of the alterations in receptor parameters which could be related, at least partially, to proportionate changes in reticulocyte count.     

Protective and ameliorative effects of maté (Ilex paraguariensis) on metabolic syndrome in TSOD mice

Yerba maté (mate) tea, a herbal tea prepared from the leaves of Ilex paraguariensis, is widely consumed in southern Latin America, and is gaining popularity worldwide. We investigated effects of an aqueous extract of mate on metabolic syndrome features in a metabolic syndrome model Tsumura Suzuki obese diabetic (TSOD) mouse. Oral administration of mate (100 mg/kg) for 7 weeks induced significant decreases in body weight, body mass index, and food intake in TSOD. It significantly decreased the hyperglycemia by reducing fasting blood glucose level, and increasing glucose uptake in glucose tolerance test. It also showed significant improvement in insulin sensitivity by increasing glucose uptake in insulin tolerance test, increasing quantitative insulin sensitivity check index, and decreasing homeostasis model assessment of insulin resistance index. The results also showed significant effects of mate on hyperlipidemia by decreasing blood levels of triglycerides, non-esterified fatty acids, and total cholesterol. Moreover, mate significantly improved adiponectin (AD) level, and exhibited significant reduction in white adipose tissue weight, and adiposity index in TSOD. It also showed significant ameliorative effects on TSOD histopathology, by reducing adipocytes proliferation, and improving hepatic steatosis. Furthermore, mate administration induced a dose-dependent delay in gastric emptying. The current data suggest that mate ameliorates metabolic syndrome by mechanisms involving increase of peripheral insulin sensitivity and cellular glucose uptake, and by modulating the level of circulating lipid metabolites and AD. These results indicate that mate can induce protective and ameliorative effects on insulin resistance, diabesity, and dyslipidemia in metabolic syndrome.     

Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial.

Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.     

Role of insulin-like growth factor iin maintaining normal glucose homeostasis

Insulin-like growth factor I (IGF-I) has significant structural homology with insulin. IGF-I has been shown to bind to insulin receptors to stimulate glucose transport in fat and muscle, to inhibit hepatic glucose output and to lower blood glucose while simultaneously suppressing insulin secretion. However, the precise role of IGF-I in maintaining normal glucose homeostasis and insulin sensitivity is not well defined. Studies in patients with diabetes have shown that in insulin-deficient states, serum IGF-I concentrations are low and increase with insulin therapy. Similarly, administration of insulin via the portal vein results in optimization of plasma IGF-I concentrations. A patient with an IGF1 gene deletion was shown to have severe insulin resistance that improved with IGF-I therapy. Studies conducted in experimental animals have shown that if IGF-I synthesis by the liver is deleted, the animals become insulin-resistant, and this is improved when IGF-I is administered. Likewise, deletion of the IGF-I receptor in muscle in mice induces severe insulin resistance. Administration of IGF-I to patients with type 2 diabetes mellitus has been shown to result in an improvement in insulin sensitivity and a reduction in the requirement for exogenously administered insulin to maintain glucose homeostasis. A polymorphism in the IGF1 gene that has been shown to reduce serum IGF-I results in an increased prevalence of type 2 diabetes. Taken together, these findings support the conclusion that IGF-I is necessary for normal insulin sensitivity, and impairment of IGF-I synthesis results in a worsening state of insulin resistance.     

Transhepatic absorption and biliary excretion of insulin

The application of insulin to the liver in rats is followed by an increase of the insulin concentration in the bile. The pathway of insulin from the liver surface to the bile may include a secretory process by the hepatic cells, or it may bypass the hepatic cells, using direct anatomical pathways from blood and lymph to bile. The concentration of insulin in arterial and venous blood, in lymph, and in bile was measured following application of insulin to the liver surface and following peritoneal or intravenous administration. The results confirm that insulin is absorbed from the surface of the liver, but the glucose modulating effect was less effective than after intravenous administration. The insulin concentration in bile was increased after insulin administration by all routes, with the highest and most prolonged increases found after intraperitoneal administration. The results suggest that following transhepatic and intravenous administration, insulin reaches the bile without passing through the liver cells.     

Effects of chronic nicotine administration on insulin, glucose, epinephrine, and norepinephrine

There is an inverse relationship between nicotine administration and body weight. Previous research indicates that this relationship results partially from effects of nicotine on energy intake. The present research includes two animal studies designed to investigate the effects of chronic nicotine administration on biochemical responses that affect energy utilization. The results indicate that chronic nicotine administration is accompanied by significant decreases in circulating insulin levels. Nicotine increases levels of catecholamines, but this effect is short-lived. The effects of nicotine on insulin are consistent with the conclusion that nicotine administration increases energy utilization.     

Effect of vanadate administration on polyol pathway in diabetic rat kidney.

Effect of oral administration of sodium orthovanadate for three weeks on polyol pathway in renal cortex and medulla was studied in control and alloxan diabetic rats. An enhancement in aldose reductase in cortex and medulla and sorbitol dehydrogenase in cortex was observed in alloxan diabetic rats. Despite depressed insulin secretion, vanadate treatment to diabetic rats counteracted hyperglycemia, normalized elevated enzyme activities and glucose level, prevented medullary sorbitol accumulation and markedly checked increase in kidney weight. These results show that vanadate causes marked improvement in renal hypertrophy and has an antidiabetogenic effect on polyol pathway in diabetic kidney.     

Comparison of local and systemic effects of insulin on myocardial glucose extraction in ischemic heart disease

Physiological increases in circulating insulin level significantly increase myocardial glucose uptake in vivo. To what extent this represents a direct insulin action on the heart or results indirectly from reduction in circulating concentrations of free fatty acids (FFA) is uncertain. To examine this, we measured myocardial glucose, lactate, and FFA extraction in 10 fasting men (ages 49-76 yr) with stable coronary artery disease during sequential intracoronary (10 mU/min, coronary plasma insulin = 140 +/- 20 microU/ml) and intravenous (100 mU/min, systemic plasma insulin = 168 +/- 26 microU/ml) insulin infusion. Basally, hearts extracted 2 +/- 2% of arterial glucose and extracted 27 +/- 6% of FFA. Coronary insulin infusion increased glucose extraction to 5 +/- 3% (P < 0.01 vs. basal) without changing plasma FFA or heart FFA extraction. Conversion to intravenous infusion lowered plasma FFA by approximately 50% and heart FFA extraction by approximately 75%, increasing heart glucose extraction still further to 8 +/- 3% (P < 0. 01 vs. intracoronary). This suggests the increase in myocardial glucose extraction observed in response to an increment in systemic insulin concentration is mediated equally by a reduction in circulating FFA and by direct insulin action on the heart itself. Coronary insulin infusion increased myocardial lactate extraction as well (from 20 +/- 10% to 29 +/- 9%, P < 0.05), suggesting the local action may include stimulation of a metabolic step distal to glucose transport and glycolysis.     

Association of an oral formulation of angiotensin-(1–7) with atenolol improves lipid metabolism in hypertensive rats

The β-adrenergic blockers and antagonists of the renin-angiotensin system (RAS) are among the drugs that present better results in the control of cardio-metabolic diseases. The aim of the present study was to evaluate the effect of the association of the β-blocker, atenolol, and an oral formulation of Ang-(1–7) on lipid metabolism in spontaneously hypertensive rats (SHR). The main results showed that SHR treated with oral formulation of Ang-(1–7) in combination to atenolol have an improvement of lipid metabolism with a reduction of total plasma cholesterol, improvement of oral fat load tolerance and an increase in the lipolytic response stimulated by the β-adrenergic agonist, isoproterenol, without modification of resting glucose or insulin sensitivity in adipocytes. In conclusion, we showed that administration of an Ang-(1–7) oral formulation in association with a β-blocker induces beneficial effects on dyslipidemia treatment associated with hypertension.     

Insulin-like effect of vanadate on malic enzyme and glucose-6-phosphate dehydrogenase activities in streptozotocin-induced diabetic rat liver

The effect of oral administration of sodium orthovanadate on hepatic malic enzyme (EC 1.1.1.40) and glucose-6-phosphate dehydrogenase (EC 1.1.1.49) activities was investigated in nondiabetic and diabetic rats. Streptozotocin-induced diabetic rats were characterized by 4.7-fold increase in plasma glucose and 82% decrease in plasma insulin levels. The activities of hepatic malic enzyme and glucose-6-phosphate dehydrogenase were also diminished (P less than 0.001). Vanadate treatment in diabetic rats led to a significant decrease (P less than 0.001) in plasma glucose levels and to the normalization of enzyme activities, but it did not alter plasma insulin levels. In nondiabetic rats vanadate decreased the plasma insulin level by 64% without altering the enzyme activities. Significant correlation was observed between plasma insulin and hepatic lipogenic enzyme activities in untreated and vanadate-treated rats. Vanadate administration caused a shift to left in this correlation suggesting improvement in insulin sensitivity.     

Comparison of the subchronic antidiabetic effects of DPP IV-resistant GIP and GLP-1 analogues in obese diabetic (ob/ob) mice.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are the two key incretin hormones released from the gastrointestinal tract that regulate blood glucose homeostasis through potent insulin secretion. The rapid degradation of GIP and GLP-1 by the ubiquitous enzyme dipeptidyl peptidase IV (DPP IV) renders both peptides noninsulinotropic. However, DPP IV stable agonists, such as N-AcGIP and (Val8)GLP-1, have now been developed. The present study has examined and compared the metabolic effects of subchronic administration of daily i.p. injections of N-AcGIP, (Val8) GLP-1 and a combination of both peptides (all at 25 nmol/kg bw) in obese diabetic (ob/ob) mice. Initial in vitro experiments confirmed the potent insulinotropic properties of N-AcGIP and (Val8)GLP-1 in the clonal pancreatic BRIN BD11 cell line. Subchronic administration of N-AcGIP, (Val8)GLP-1 or combined peptide administration had no significant effects on the body weight, food intake and plasma insulin concentrations. However, all treatment groups had significantly (p < 0.05) decreased plasma glucose levels and improved glucose tolerance by day 14. The effectiveness of the peptide groups was similar, and glucose concentrations were substantially reduced following injection of insulin to assess insulin sensitivity compared to control. These results provide evidence for an improvement of glucose homeostasis following treatment with enzyme-resistant GIP and GLP-1 analogues.