Serum, zinc, copper and insulin in diabetes mellitus

We studied serum zinc, copper, ceruloplasmin, insulin, basal glycemia and cholesterol in 49 diabetics on oral anti-diabetic agent and in 10 normal people. We found there is an elevation of serum zinc, copper and ceruloplasmin in the diabetic group that is statistically significant (p less than 0.001). There is a significant correlation between zinc and insulin (p less than 0.001), and between the quotient zinc/copper and cholesterol (p less than 0.001). The increase of plasma zinc can reflect a deficient storage or a chronic hypersecretion of insulin in hyperglucemic patients. We think that the quotient zinc/copper/might play a role in the pathogenesis of the arteriosclerosis in diabetes.     

Sex hormones, insulin sensitivity, and diabetes mellitus

Sex differences and the role of gonadal hormones in modulating insulin sensitivity and glucose tolerance are of increasing interest and importance because of the increasing prevalence of type 2 diabetes mellitus and the metabolic abnormalities associated with aging. Body composition is closely associated with insulin sensitivity, and increased body fat, particularly in the visceral compartment, is a risk factor for developing type 2 diabetes mellitus. Sex differences in body composition and/or insulin sensitivity are evident in humans throughout the lifespan. Ovarian hormones influence insulin sensitivity across the menstrual cycle, during pregnancy, and in the menopausal transition. Similarly, estrogens and progestins used for contraception and hormone replacement therapy affect glucoregulation. Nonhuman primates and humans have similar life histories and reproductive characteristics. As a result, nonhuman primates provide a valuable model for investigating factors related to insulin sensitivity. Studies of nonhuman primates have contributed significantly to our understanding of sex differences and the influence of sex steroids in this context. This brief review surveys present knowledge of the sex differences in body composition, insulin sensitivity, and risk for development of type 2 diabetes mellitus derived from studies in humans and nonhuman primates. The influences of endogenous and exogenous gonadal steroids are emphasized.     

Renal enzymes during experimental diabetes mellitus in the rat. Role of insulin, carbohydrate metabolism, and ketoacidosis

The activities of various ammoniagenic, gluconeogenic, and glycolytic enzymes were measured in the renal cortex and also in the liver of rats made diabetic with streptozotocin. Five groups of animals were studied: normal, normoglycemic diabetic (insulin therapy), hyperglycemic, ketoacidotic, and ammonium chloride treated rats. Glutaminase I, glutamate dehydrogenase, glutamine synthetase, phosphoenolpyruvate carboxykinase (PEPCK), hexokinase, phosphofructokinase, fructose-1,6-diphosphatase, malate dehydrogenase, malic enzyme, and lactate dehydrogenase were measured. Renal glutaminase I activity rose during ketoacidosis and ammonium chloride acidosis. Glutamate dehydrogenase in the kidney rose only in ammonium chloride treated animals. Glutamine synthetase showed no particular variation. PEPCK rose in diabetic hyperglycemic animals and more so during ketoacidosis and ammonium chloride acidosis. It also rose in the liver of the diabetic animals. Hexokinase activity in the kidney rose in diabetic insulin-treated normoglycemic rats and also during ketoacidosis. The same pattern was observed in the liver of these diabetic rats. Renal and hepatic phosphofructokinase activities were elevated in all groups of experimental animals. Fructose-1,6-diphosphatase and malate dehydrogenase did not vary significantly in the kidney and the liver. Malic enzyme was lower in the kidney and liver of the hyperglycemic diabetic animals and also in the liver of the ketoacidotic rats. Lactate dehydrogenase fell slightly in the liver of diabetic hyperglycemic and NH4Cl acidotic animals. The present study indicates that glutaminase I is associated with the first step of increased renal ammoniagenesis during ketoacidosis. PEPCK activity is influenced both by hyperglycemia and ketoacidosis, acidosis playing an additional role. Insulin appears to prevent renal gluconeogenesis and to favour glycolysis. The latter would seem to remain operative in hyperglycemic and ketoacidotic diabetic animals.     

Somatostatin antagonist analog increases GH, insulin, and glucagon release in the rat

We have utilized the relative structural simplicity of several short, cyclic, highly active somatostatin analogs in the search for competitive antagonists of somatostatin. During an attempted synthesis of cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr), catalytic hydrogenation of the protected peptide intermediate unexpectedly gave cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] in which the benzyl protecting group on Thr could not be removed even upon prolonged treatment under standard conditions. Injection of this new peptide into the rat completely blocked the inhibitory effects of exogenous somatostatin on GH, insulin, and glucagon release. Indeed, in fasted rats, basal hepatic portal insulin and glucagon levels were significantly increased after analog treatment. Plasma GH levels in Nembutal-anesthetized and stimulated rats were also increased after injection of the analog. These results provide strong evidence that endogenous somatostatin exerts local tonic control of pituitary and pancreatic secretions. The availability of a somatostatin anatagonist should be of considerable value in elucidating the roles of somatostatin in these and many other physiological processes.     

A portable, pre-programmable insulin infusion system in diabetes mellitus.

A miniaturized portable pump has been developed in order to study the effects of pre-programmed insulin infusion patterns on the blood glucose levels in juvenile-onset, insulin-requiring diabetics. Six diabetics undergoing 7 insulin infusion periods of up to 4 days were studied. The mean blood glucose was 7.0 +/- 2.3 (SD) mmol/l and the mean amplitude of glycemic excursions was 5.0 +/- 1.4 mmol/l. Success in achieving normoglycemia will depend on choosing the correct dose of insulin for infusion.     

Superiority of insulin analogues versus human insulin in the treatment of diabetes mellitus

The modern goals of insulin replacement in Type 1 and Type 2 diabetes mellitus (T1, T2DM) are A1C <6.5% long-term, and prevention of hypoglycaemia (blood glucose, BG <70 mg/dl). In addition to appropriate education and motivation of diabetic subjects, the use of rapid- and long-acting insulin analogues, is critical to achieve these goals. The benefits of rapid-acting analogues (lispro, aspart and glulisine have similar pharmacodynamic effects) compared with non-modified human regular insulin, are: (a) lower 1- and 2-h post-prandial blood glucose; (b) lower risk of late post-prandial hypoglycaemia (and therefore lower BG variability); (c) better quality of life (greater flexibility in timing and dosing of insulin). In T1DM, rapid-acting analogues improve A1C only by the extent to which replacement of basal insulin is optimized at the same time, either by multiple daily NPH administrations, or continuous subcutaneous insulin infusion (CSII), or use of the long-acting insulin analogues glargine or detemir. In T2DM, rapid-acting analogues reduce post-prandial hyperglycaemia more than human regular insulin, but systematic studies are needed to examine the effects on A1C. The benefits of long-acting insulin analogues glargine and detemir vs. NPH, are: (1) lower fasting BG combined with lower risk of hypoglycaemia in the interprandial state (night); (2) lower variability of BG. Glargine and detemir differ in terms of potency and duration of action. Detemir should be given twice daily in the large majority of people with T1DM, and in a large percentage of subjects with T2DM as well, usually at doses greater vs those of the once daily glargine. However, when used appropriately for individual pharmacokinetics and pharmacodynamics, glargine and detemir result into similar effects on BG, risk of hypoglycaemia and A1C. Rapid- and long-acting insulin analogues should always be combined in the treatment of T1 and T2DM.     

Cost-effectiveness of insulin analogues for diabetes mellitus

Background

Insulin analogues may be associated with fewer episodes of hypoglycemia than conventional insulins. However, they are costly alternatives. We compared the cost-effectiveness of insulin analogues and conventional insulins used to treat type 1 and type 2 diabetes mellitus in adults.

Methods

We conducted a cost-effectiveness evaluation of insulin analogues versus conventional insulins using the Center for Outcomes Research Diabetes Model. We compared rapid-acting analogues (insulin aspart and insulin lispro) with regular human insulin, and long-acting analogues (insulin glargine and insulin detemir) with neutral protamine Hagedorn insulin. We derived clinical information for the comparisons from meta-analyses of randomized controlled trials. We obtained cost and utility estimates from published sources. We performed sensitivity analyses to test the robustness of our results.

Results

For type 1 diabetes, insulin aspart was more effective and less costly than regular human insulin. Insulin lispro was associated with an incremental cost of Can$28 996 per quality-adjusted life-year. The incremental cost per quality-adjusted life-year was Can$87 932 for insulin glargine and Can$387 729 for insulin detemir, compared with neutral protamine Hagedorn insulin. For type 2 diabetes, insulin aspart was associated with an incremental cost of Can$22 488 per quality-adjusted life-year compared with regular human insulin. For insulin lispro, the incremental cost was Can$130 865. Compared with neutral protamine Hagedorn insulin, insulin detemir was less effective and more costly. Insulin glargine was associated with an incremental cost of Can$642 994 per quality-adjusted life-year. The model was sensitive to changes in the effect size of hemoglobin A_1c and to decrements applied to utility scores when fear of hypoglycemia was included as a factor.

Interpretation

The cost-effectiveness of insulin analogues depends on the type of insulin analogue and whether the patient receiving the treatment has type 1 or type 2 diabetes. With the exception of rapid-acting insulin analogues in type 1 diabetes, routine use of insulin analogues, especially long-acting analogues in type 2 diabetes, is unlikely to represent an efficient use of finite health care resources.Insulin agents available for the treatment of diabetes mellitus include conventional insulins and insulin analogues. Insulin analogues were developed to mimic more closely the separate bolus and basal components of insulin secretion.¹ Rapid-acting (bolus or mealtime) and long-acting (basal or background) analogue formulations are available. This new class of drugs has been promoted as providing more flexible treatment schedules and a reduced risk of hypoglycemia relative to conventional insulins.¹The cost of insulin analogues exceeds that of conventional insulins.^2,3 More than US$7.3 billion was spent globally on the purchase of insulin products in 2005 — an increase of 19% over the previous year.⁴ It has been suggested that the increased expenditure was due to both the increasing prevalence of diabetes and the increased use of insulin analogues.⁵We performed an analysis of the cost-effectiveness of insulin analogues compared with conventional insulins in the management of type 1 or type 2 diabetes in adults.     

Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance

Type 2 diabetes is characterized by cellular and extracellular Mg depletion. Epidemiologic studies showed a high prevalence of hypomagnesaemia and lower intracellular Mg concentrations in diabetic subjects. Insulin and glucose are important regulators of Mg metabolism. Intracellular Mg plays a key role in regulating insulin action, insulin-mediated-glucose uptake and vascular tone. Reduced intracellular Mg concentrations result in a defective tyrosine-kinase activity, post-receptorial impairment in insulin action, and worsening of insulin resistance in diabetic patients. Mg deficit has been proposed as a possible underlying common mechanism of the "insulin resistance" of different metabolic conditions. Low dietary Mg intake is also related to the development of type 2 diabetes. Benefits of Mg supplementation on metabolic profile in diabetic subjects have been found in most, but not all clinical studies, and larger prospective studies are needed to support the potential role of dietary Mg supplementation as a possible public health strategy in diabetes risk.     

Effect of type-1 diabetes mellitus on the regulation of insulin and endothelin-1 receptors in rat hearts

This project assesses the treatment role with insulin and (or) angiotensin II receptor subtype-1 (AT1-R) blocker (ARB) on insulin receptor and endothelin-1 receptor subtype (ETA-R and ETB-R) regulation in rat hearts suffering from insulin-dependent diabetes mellitus (IDDM). Animals were divided into 6 groups: groups 1, 3, and 5 were controls consisting of normal, diabetic (streptozotocin-treated, once at 0 time), and diabetic supplemented daily with insulin, respectively, whereas groups 2, 4, and 6 were the controls treated daily with losartan. One month after enrollment, rats were sacrificed and samples of cardiac tissue were snapped frozen for immunostaining and Western blotting. Insulin receptor density was observed to be upregulated in the cardiomyocytes of diabetic animals, but downregulated with insulin supplementation alone. Cotreatment with insulin and an ARB resulted in drastic increase in insulin-receptor density in the diabetic rats. In addition, expression of ETA-R in cardiomyocytes was upregulated and was consistently maintained within the various treatment modalities. However, ETB-R expression was significantly reduced in the diabetic group treated with both insulin and an ARB. The changes in the expression of the insulin, the ETA-Rs, and the ETB-Rs at the various sites of the myocardium and the effect of both insulin treatment and blockade of the AT1-R explain the new benefits related to the halting of myocardial remodeling in IDDM rats.     

The role of rapid-acting insulin analogues and inhaled insulin in type 2 diabetes mellitus

sBackground:The availability of rapid-acting insulin analogues and inhaled insulin gives clinicians additional treatmentoptions in the management of patients with diabetes mellitus (DM). Combining rapid-acting insulin analogues with basal insulin can more closely mimic physiologic insulin release to maximize glycemic control.Objective:The objective of this article was to discuss the role of rapid-acting insulin analogues and inhaled insulin inthe treatment of patients with type 2 DM.Methods:Materials for this article were obtained through an online search of MEDLINE/PubMed and Google(1996-2006) using the search terms bolus insulin, postprandial, rapid-acting insulin analogues, titration, hypoglycemia, glycemic control, inhaled insulin, and insulins lispro, aspart, and glulisine.Results:Glycosylated hemoglobin (A1C) levels and number of all hypoglycemic episodes were similar in patients withtype 2 DM taking either mealtime rapid-acting insulin analogues or regular human insulin (RHI). Rapid-acting insulins have been successfully used in basal-bolus regimens with a variety of long- and intermediate-acting insulins, as well as with oral hypoglycemic agents. Injectable rapid-acting insulin analogues markedly decreased postprandial glucose (PPG) levels compared with RHI. Better reduction in PPG levels may be key to achieving target A1C levels in some patients, but long-term outcome studies are needed to assess whether lowering PPG levels decreases cardiovascular risk in patients with type 2 DM. Inhaled insulin may be an option for patients who cannot inject insulin, but route of administration and dosing issues limit its use in many patients. The effect of inhaled insulin on PPG is unclear at this time.Conclusions:Although rapid-acting insulin analogues are effective in the management of patients with type 2 DM, the limited numbers of studies have yet to demonstrate that these agents have any significant long-term advantage compared with RHI. In addition, they cost more than RHI. Further studies are needed to compare the efficacy of the rapid-acting insulin analogues, to compare the different dosing regimens used with mealtime insulin administration, and to ascertain if the decrease in PPG levels seen with the use of rapid-acting insulin analogues translates into improved glycemic control and perhaps even a reduction in cardiovascular risk in patients with type 2 DM. (Insulin. 2007;2:61-67) Copyright 2007 Excerpta Medica, Inc.     

Changes in insulin secretion after secretin administration and the implications in diabetes mellitus

Secrepan (Eisai Co. Tokyo, Japan) was administered to 9 healthy volunteers and 36 patients with non-insulin dependent diabetes mellitus (NIDDM) to clarify the effect of secretin on the pancreatic B-cell, by determining the changes in blood of insulin (IRI). Whereas IRI in healthy subjects showed a monophasic change, reaching a peak (delta IRI = 43 +/- 7.3 microunits/ml, M +/- SE) 5 min after secretin loading and returning to the basal level in 15 min, NIDDM patients on diet therapy (delta IRI = 40.2 +/- 7.6 microunits/ml) showed no significant difference from the control group, but NIDDM patients on sulfonylurea (SU) (15.5 +/- 2.4 microunits/ml) and those on insulin therapy (5.3 +/- 1.4 microunits/ml), both showed a significant depression in responsiveness. Further, the changes in insulin secretion after atropine administration in healthy subjects and the changes in IRI response to Secrepan in vagotomized patients were also determined. As a result, data which preclude the possibility of association of the vagus nerve and cholinergic nerve with the stimulation of insulin secretion by secretin were obtained, and a direct action of secretin on the cell of islets of Langerhans was suggested. The maximum IRI response after a secretin load had a significant positive correlation with the IRI response after a 75-gm GTT and the content of C-peptide immunoreactivity in 24-hour urine. Therefore, insulin response to a secretin load can be useful in assessing endogenous insulin secretion and provides a pertinent clinical guide for the selection of an appropriate therapy for diabetes mellitus.     

Role of insulin,adenosine, and adipokine receptors in the foetoplacental vascular dysfunction in gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with maternal and foetal hyperglycaemia and altered foetoplacental vascular function. Human foetoplacental microvascular and macrovascular endothelium from GDM pregnancy show increased maximal l-arginine transport capacity via the human cationic amino acid transporter 1 (hCAT-1) isoform and nitric oxide (NO) synthesis by the endothelial NO synthase (eNOS). These alterations are paralleled by lower maximal transport activity of the endogenous nucleoside adenosine via the human equilibrative nucleoside transporter 1 (hENT1) and activation of adenosine receptors. A causal relationship has been described for adenosine-activation of A_2A adenosine receptors, hCAT-1, and eNOS activity (i.e. the Adenosine/l-Arginine/Nitric Oxide, ALANO, signalling pathway). Insulin restores these alterations in GDM via activation of insulin receptor A (IR-A) form in the macrovascular but IR-A and IR-B forms in the microcirculation of the human placenta. Adipokines are secreted from adipocytes influencing the foetoplacental metabolic and vascular function. Various adipokines are dysregulated in GDM, with adiponectin and leptin playing major roles. Abnormal plasma concentration of these adipokines and the activation or their receptors are involved in the pathophysiology of GDM. However, involvement of adipokines, adenosine, and insulin receptors and membrane transporters in the aetiology of this disease of pregnancy is unknown. This review focuses on the pathophysiology of insulin and adenosine receptors and l-arginine and adenosine membranes transporters giving an overview of the key adipokines leptin and adiponectin in the foetoplacental vasculature in GDM. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia.