Effects of insulin and other antihyperglycaemic agents on lipid profiles of patients with diabetes.

Increased morbidity and mortality risk due to diabetes-associated cardiovascular diseases is partly associated with hyperglycaemia as well as dyslipidaemia. Pharmacological treatment of diabetic hyperglycaemia involves the use of the older oral antidiabetic drugs [OADs: biguanides, sulphonylureas (SUs), α-glucosidase inhibitors and thiazolidinediones], insulin (human and analogues) and/or incretin-based therapies (glucagon-like peptide-1 analogues and dipeptidyl peptidase 4 inhibitors). Many of these agents have also been suggested to improve lipid profiles in patients with diabetes. These effects may have benefits on cardiovascular risk beyond glucose-lowering actions. This review discusses the effects of OADs, insulins and incretin-based therapies on lipid variables along with the possible mechanisms and clinical implications of these findings. The effects of intensive versus conventional antihyperglycaemic therapy on cardiovascular outcomes and lipid profiles are also discussed. A major conclusion of this review is that agents within the same class of OADs can have different effects on lipid variables and that contrary to the findings in experimental models, insulin has been shown to have beneficial effects on lipid variables in clinical trials. Further studies are needed to understand the precise effect and the mechanisms of these effects of insulin on lipids.

A practical guide to male hypogonadism in the primary care setting.

There is a high prevalence of hypogonadism in the older adult male population and the proportion of older men in the population is projected to rise in the future. As hypogonadism increases with age and is significantly associated with various comorbidities such as obesity, type 2 diabetes, hypertension, osteoporosis and metabolic syndrome, the physician is increasingly likely to have to treat hypogonadism in the clinic. The main symptoms of hypogonadism are reduced libido/erectile dysfunction, reduced muscle mass and strength, increased adiposity, osteoporosis/low bone mass, depressed mood and fatigue. Diagnosis of the condition requires the presence of low serum testosterone levels and the presence of hypogonadal symptoms. There are a number of formulations available for testosterone therapy including intramuscular injections, transdermal patches, transdermal gels, buccal patches and subcutaneous pellets. These are efficacious in establishing eugonadal testosterone levels in the blood and relieving symptoms. Restoration of testosterone levels to the normal range improves libido, sexual function, and mood; reduces fat body mass; increases lean body mass; and improves bone mineral density. Testosterone treatment is contraindicated in subjects with prostate cancer or benign prostate hyperplasia and risks of treatment are perceived to be high by many physicians. These risks, however, are often exaggerated and should not outweigh the benefits of testosterone treatment.

A study of the effect of yoga training on pulmonary functions in patients with bronchial asthma.

The role of yoga breathing exercises, as an adjunct treatment for bronchial asthma is well recognized. One hundred twenty patients of asthma were randomized into two groups i.e Group A (yoga training group) and Group B (control group). Each group included sixty patients. Pulmonary function tests were performed on all the patients at baseline, after 4 weeks and then after 8 weeks. Majority of the subjects in the two groups had mild disease (34 patients in Group A and 32 in Group B). Group A subjects showed a statistically significant increasing trend (P < 0.01) in % predicted peak expiratory flow rate (PEFR), forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), forced mid expiratory flow in 0.25-0.75 seconds (FEF25-75) and FEV1/FVC% ratio at 4 weeks and 8 weeks as compared to Group B. Thus, yoga breathing exercises used adjunctively with standard pharmacological treatment significantly improves pulmonary functions in patients with bronchial asthma.

Hypogonadotrophic hypogonadism in type 2 diabetes.

Recent work shows a high prevalence of low testosterone and inappropriately low luteinizing hormone (LH) and follicle stimulating hormone (FSH) concentrations in type 2 diabetes. This syndrome of hypogonadotrophic hypogonadism (HH) is associated with obesity in patients with type 2 diabetes. However, the duration of diabetes or HbA1c are not related to HH. Furthermore, recent data show that HH is not associated with type 1 diabetes. C-reactive protein concentrations have been shown to be elevated in patients with HH and are inversely related to plasma testosterone concentrations. This inverse relationship between plasma free testosterone and C- reactive protein concentrations in patients with type 2 diabetes suggests that inflammation may play an important role in the pathogenesis of this syndrome. This is of interest since inflammatory mechanisms may have a cardinal role in the pathogenesis of insulin resistance. It is also relevant that in the mouse, deletion of the insulin receptor in neurons leads to HH in addition to a state of systemic insulin resistance. It has also been shown that insulin facilitates the secretion of gonadotrophin releasing hormone (GnRH) from neuronal cell cultures. Thus, HH may be the result of insulin resistance at the level of the GnRH secreting neuron. Low testosterone concentrations are also related to an increase in total and regional adiposity. This review discusses these issues and attempts to make the syndrome relevant as a clinical entity. Clinical trials are required to determine whether testosterone replacement alleviates insulin resistance and inflammation. In addition, low testosterone levels are associated with an increase in cardiovascular events. Testosterone therapy may therefore, reduce cardiovascular risk. This important aspect requires further investigation.

Angiotensin II and inflammation: the effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockade.

Angiotensin II (Ang II) increases adhesion molecules, cytokines and chemokines and exerts a proinflammatory effect on leucocytes, endothelial cells and vascular smooth muscle cells. Acting via the type 1 receptor, Ang II initiates an inflammatory cascade of reduced nicotinamide-adenine dinucleotide phosphate oxidase, reactive oxygen species (ROS) and nuclear factor-kappaB, which mediates transcription and gene expression and increases adhesion molecules and chemokines. An excess of ROS decreases nitric oxide bioavailability, causes endothelial dysfunction, and promotes atherosclerosis. Moreover, Ang II interrupts the anti-inflammatory effects of insulin. Together, these effects promote a prothrombotic state as well as plaque rupture. Ang II receptor blockers suppress mediators of inflammation, including ROS and C-reactive protein, and they increase expression of inhibitory kappaB (an inhibitor of nuclear factor-kappaB). These anti-inflammatory and antioxidative effects, which are probably due in part to unopposed stimulation of the Ang II type 2 receptor, may be beneficial in acute coronary syndromes and may also contribute to the prevention of type II diabetes mellitus, as insulin resistance is mediated by inflammatory processes.

Elevated production of active oxygen in Bloom's syndrome cell lines.

Based on our previous evidence indicating that the elevated sister chromatid exchange that characterizes Bloom syndrome (BS) cells may arise in response to elevated production of active oxygen, we have quantitated the levels of active oxygen in two control, two BS and one BS revertant cell lines. Luminol-dependent chemiluminescence was used as a measure of active oxygen production following treatment of the cells with the calcium ionophore A23187 or the chemotactic tripeptide N-formylmethionylleucylphenylalanine. A peptide factor present in plasma was required for priming the cells to undergo the oxidative response. As determined with A23187, active oxygen production was elevated in BS cell lines by 48.6% above control. Using N-formylmethionylleucylphenylalanine, active oxygen production was found to be increased by 250-314%. Chemiluminescence was inhibited in a dose-dependent manner by diphenylene iodonium, which specifically binds to and inhibits membrane-associated NADPH oxidase activity. This compound inhibited oxygen radical production nearly 3 times more effectively in control cells than in BS cells. The capacity to produce elevated levels of oxygen radicals may contribute to the spontaneous chromosomal instability of BS cells and to the associated high incidence of neoplasia in individuals with BS.

Estrogen receptor-alpha in the inhibition of cancer growth and angiogenesis.

A high level of estrogen receptor-alpha (ER-alpha) is believed to be favorable in the prognosis and treatment of certain female cancers. ER-alpha expression in the ER-negative breast cancer cell lines inhibits their proliferation and invasive, metastatic potential in vitro. We stably overexpressed the ER-alpha in the human endometrial cancer cell line Ishikawa and showed that, unlike estradiol, high levels of ER-alpha significantly inhibit the growth of tumors xenografted from the Ishikawa cells. Subsequent to ER-alpha overexpression, in vivo down-regulation of vascular endothelial growth factor was observed in tumor xenografts. In addition, these tumors showed an inhibition of vascularization and of the angiogenic agent, integrin alphavbeta3. Involvement of a switch in the angiogenic pathways during tumorigenesis has been a recent focus of interest. Our results indicate that a high level of ER-alpha may be beneficial in the control of female cancers because of its inhibitory effect on such angiogenic pathways.

Carvedilol inhibits reactive oxygen species generation by leukocytes and oxidative damage to amino acids.

BACKGROUND: The purpose of this study was to test whether carvedilol has an antioxidant effect in humans in vivo. METHODS AND RESULTS: We administered 3.125 mg of carvedilol twice daily to normal subjects for 1 week. ROS generation by polymorphonuclear leukocytes and mononuclear cells fell from 314+/-183.43 and 303+/-116 mV to 185+/-157 and 189+/-63 mV (P<0.025), respectively. m-Tyrosine fell from 4.24+/-0.99 to 4.03+/-0.97 ng/mL (P=0.01), and o-tyrosine fell from 4.59+/-1.10 to 4.24+/-0.99 ng/mL (P=0.004) in the absence of a change in phenylalanine concentrations. CONCLUSIONS: We conclude that carvedilol significantly inhibits ROS generation by leukocytes and oxidative conversion of phenylalanine to m- and o-tyrosine.

Octreotide acetate long-acting formulation versus open-label subcutaneous octreotide acetate in malignant carcinoid syndrome.

PURPOSE: Subcutaneous (SC) octreotide acetate effectively relieves the diarrhea and flushing associated with carcinoid syndrome but requires long-term multiple injections daily. A microencapsulated long-acting formulation (LAR) of octreotide acetate has been developed for once-monthly intramuscular dosing. PATIENTS AND METHODS: A randomized trial compared double-blinded octreotide LAR at 10, 20, and 30 mg every 4 weeks with open-label SC octreotide every 8 hours for the treatment of carcinoid syndrome. Seventy-nine patients controlled with treatment of SC octreotide 0.3 to 0.9 mg/d whose symptoms returned during a washout period and who returned for at least the week 20 evaluation constituted the efficacy-assessable population. RESULTS: Complete or partial treatment success was comparable in each of the four arms of the study (SC, 58.3%; 10 mg, 66.7%; 20 mg, 71.4%; 30 mg, 61.9%; P> or =.72 for all pairwise comparisons). Control of stool frequency was similar in all treatment groups. Flushing episodes were best controlled in the 20-mg LAR and SC groups; the 10-mg LAR treatment was least effective in the control of flushing. Treatment was well tolerated by patients in all four groups. CONCLUSION: Once octreotide steady-state concentrations are achieved, octreotide LAR controls the symptoms of carcinoid syndrome at least as well as SC octreotide. A starting dose of 20 mg of octreotide LAR is recommended. Supplemental SC octreotide is needed for approximately 2 weeks after initiation of octreotide LAR treatment. Occasional rescue SC injections may be required for possibly 2 to 3 months until steady-state octreotide levels from the LAR formulation are achieved.

Insulin-like effect of zinc on adipocytes.

In view of the known effect of zinc on the crystalline nature of insulin, we have investigated whether zinc alters the biologic potency of this hormone. Using the rate of lipogenesis by rat epididymal adipocytes as an index of the biologic potency of insulin, we have shown that zinc exerts a potent stimulatory effect upon lipogenesis in vitro similar to, but quite independently of, insulin and that it has an additive effect with that of insulin when both are incubated together. This effect of zinc on adipocytes and the biologic potency of insulin, hitherto unreported, is of significance at the biologic, pharmacologic, and clinical level.

Ethanol and its novel metabolites inhibit insulin action on adipocytes.

The effects of ethanol, acetaldehyde, and the two novel metabolites of ethanol 2,3-butanediol and 1,2-propanediol on basal and insulin-stimulated adipocyte lipogenesis and glucose oxidation in vitro were investigated. Whereas ethanol and acetaldehyde inhibited both processes at concentrations far greater than those found in alcoholic subjects, the two diols were extremely potent inhibitors of basal and insulin-stimulated adipocyte metabolism at concentrations far below those observed in alcoholic subjects. The incorporation of labeled glucose into the fatty acid moiety and glucose oxidation were inhibited at lower concentrations (0.25 microM) than those required to inhibit the incorporation of the labeled glucose into glycerol. The diols are therefore potent inhibitors of basal and insulin-stimulated adipocyte metabolism. This effect may be relevant to the pathogenesis of insulin resistance in alcoholic subjects.

Simulating the diabetic environment modifies in vitro prostacyclin synthesis.

To explain the contradictory data on the secretion of prostacyclin (PGI2) in clinical and experimental diabetes, we have investigated the effect of each of the major metabolic abnormalities in uncontrolled diabetes on vascular PGI2 synthesis. An increase in fatty acid concentrations caused a dose-dependent inhibition of PGI2 synthesis by rat aortic rings in vitro; linoleic and linolenic acids were consistently the most and palmitic the least inhibitory. Glucose had a stimulatory effect between 10 and 30 mmol/L, but a progressive fall in stimulation occurred at higher concentrations. Insulin was inhibitory at 10 and 50 mU/L; however, in combination with glucose (10 mmol/L) it was significantly stimulatory (at 10 mU/L) when the aortic rings were preincubated for 2 and 4 h. A pH of 7.0 or less was significantly inhibitory, whereas ketone bodies had no significant effect on PGI2 synthesis. These data show for the first time that altered metabolic factors in uncontrolled diabetes may have different effects on vascular PGI2 synthesis. These data help explain the variability of observations related to PGI2 synthesis and secretion in diabetes, and advocate a more detailed definition of the metabolic status of patients/animals used in such experiments.

Effect of vitamin E supplementation on platelet thromboxane A2 production in type I diabetic patients. Double-blind crossover trial.

Vitamin E deficiency is associated with increased platelet aggregation, which can be normalized through vitamin E supplementation. In diabetes, increased platelet thromboxane A2 (TXA2) production is correlated with decreased platelet vitamin E content. We therefore investigated the effect of 400 mg DL-alpha-tocopherol acetate daily for 4 wk on ADP- and collagen-induced platelet aggregation and platelet TXA2 production in 22 type I (insulin-dependent) diabetic patients without macroangiopathy and with no or only minimal microangiopathy by a double-blind placebo-controlled crossover study. Platelet aggregation was induced in platelet-rich plasma by two or three different concentrations of ADP and collagen. TXA2 was measured by the stable spontaneous breakdown product thromboxane B2 by a specific radioimmunoassay. Whereas metabolic control remained unchanged during the study period, platelet TXA2 production was significantly (P less than .05 and P less than .01) reduced at each ADP concentration and at two of three collagen concentrations. Because increased TXA2 production of diabetic platelets is thought to play an important pathogenetic role in diabetic angiopathy, we conclude that vitamin E treatment could be beneficial with respect to platelet-vessel-wall interaction and thus might be promising for the prevention of diabetic angiopathy.

Insulin-like stimulatory effect of human immunoglobulin G on adipocyte lipogenesis.

An investigation into the possible effect of thyroid stimulating immunoglobulin G on lipogenesis by adipocytes led to the discovery that all human IgGs exerted an insulin-like stimulatory effect of lipogenesis by rat adipocytes in vitro. Highly purified polyclonal IgGs prepared from normal subjects had stimulatory potencies similar to those of monoclonal IgGs obtained from patients with IgG myeloma. However, whole sera from myeloma patients with elevated IgG concentrations had a significantly higher stimulatory effect on adipocyte lipogenesis than control sera. These observations provide the first evidence that human IgG has an insulin-like metabolic effect, and that this effect is probably exerted by a nonspecific nonvariable portion of the IgG molecule. IgG may thus contribute to the non-suppressible insulin-like activity in the serum.

Transcutaneous oxygen tension in legs and feet of diabetic patients.

Transcutaneous oxygen tension (tcPO2) of the legs and feet was measured at 37 and 44 degrees C in 21 patients with diabetes mellitus, 9 of whom had peripheral neuropathy. At 37 degrees C, tcPO2 in the legs and feet of diabetic patients with peripheral neuropathy was significantly higher (P less than .02) than in control subjects and diabetic patients without neuropathy. Whereas tcPO2 in the legs of control subjects and nonneuropathic diabetic patients was greater than in the feet (P less than .02), this leg-to-foot difference was absent in diabetic patients with neuropathy. After an increase in skin temperature to 44 degrees C, tcPO2 increased in the legs and feet of all three groups, but the increase was smallest in diabetic patients with neuropathy and greatest in control subjects. In neuropathic (P less than .02) and nonneuropathic (P less than .02) diabetic patients, tcPO2 was significantly lower than in control subjects. These data are consistent with a loss of vasoconstrictor tone in the blood vessels perfusing skin and subcutaneous tissue at 37 degrees C and an inability of these vessels to vasodilate and increase blood flow at 44 degrees C in diabetic patients in general and neuropathic diabetic patients in particular. This inability to increase tcPO2 after an increase in temperature and possibly other vasodilatory stimuli may contribute to the pathogenesis of nonhealing ulcers, protracted infections, and gangrene, which characterize the diabetic foot.

Severe myopathy associated with vitamin D deficiency in western New York.

Five cases of severe myopathy associated with vitamin D deficiency are described. Each patient was confined to a wheelchair because of weakness and immobility. Two were elderly, 1 was a 37-year-old African American with type 1 diabetes mellitus, 1 was being treated for carcinoid syndrome, and 1 was severely malnourished due to poor oral intake. In each, weakness had previously been attributed to other causes, including old age, concomitant diabetic neuropathy, or general debility. Correct diagnosis was made initially by a high index of suspicion, following the demonstration of clinical proximal myopathy; confirmation was made by the demonstration of low 25-hydroxyvitamin D and elevated parathyroid hormone concentrations. Treatment with vitamin D caused a resolution of body aches and pains and a restoration of normal muscle strength in 4 to 6 weeks. Four patients became fully mobile and had normal 25-hydroxyvitamin D concentrations, and the fifth also became mobile. In the 4 fully recovered cases, parathyroid hormone levels on follow-up were lower but still elevated. This finding suggests a degree of autonomy of parathyroid secretion known to occur in cases of long-standing vitamin D deficiency. Myopathy, due to chronic vitamin D deficiency, probably contributes to immobility and ill health in a significant number of patients in the northern United States. An awareness of this condition may significantly improve mobility and quality of life in patient populations vulnerable to vitamin D deficiency.

Comparison of biologic potency of human insulin (recombinant DNA) and purified porcine insulin (PPI) on the rat and human adipocyte lipogenesis model.

To assess whether human insulin (recombinant DNA) is superior to porcine insulin, we compared the biologic effect of these two insulin preparations on rat and human adipocyte lipogenesis in vitro. The biologic potency of these two insulin preparations was similar on both human and rat adipocytes. Iodination of human and porcine insulin with 125I at A14 position led to a significant but similar loss of potency of both insulin preparations.

Diarrhea and metformin in a diabetic clinic.

In a questionnaire-based survey of 285 randomly selected diabetic patients, diarrhea was found to occur in 8%; this was found to be similar to that in 150 nondiabetic control patients attending other medical clinics (8%). When the diabetic patients were divided into separate therapeutic groups, metformin-treated (with or without sulfonylureas) patients had a markedly greater prevalence of diarrhea (20%) than those not on this drug (6%). A majority of patients with metformin-associated diarrhea had soiling of clothes as a problem, while at least two complained of frank loss of control over their anal sphincter. These patients did not have autonomic neuropathy, and in all who stopped this drug, diarrhea settled within 2-5 days. Only 6% of insulin-dependent diabetic individuals (IDD) had diarrhea, one of whom had explosive nocturnal stools with incontinence and features diagnostic of autonomic neuropathy. Metformin is by far the commonest cause of diarrhea and incontinence in our diabetic clinic, where it is used routinely. In contrast, diarrhea due to autonomic neuropathy is rare.

Sperm function and structure and seminal plasma prostanoid concentrations in men with IDDM.

Semen from 18 men with insulin-dependent diabetes mellitus (IDDM) aged 20-40 yr was compared with that from 15 age-matched control subjects. Although semen volume, sperm count, and spermatozoal motility were similar in the two groups, semen from diabetic men had significantly greater numbers of abnormal spermatozoa and significantly lower ability to penetrate hamster eggs. Concentrations of prostaglandins E2, F2 alpha, and I2 and thromboxane A2 were significantly elevated in the seminal plasma from semen of diabetic subjects compared with control subjects. These observations indicate the need for a careful assessment of fertility in diabetic men, the mechanisms underlying the abnormalities in spermatozoa, and the relationship of these abnormalities to the increase in prostanoid concentrations in diabetic men.

Muscle blood flow in diabetes mellitus. Evidence of abnormality after exercise.

OBJECTIVE: To determine whether muscle blood flow before and after exercise is abnormal in patients with diabetes mellitus. RESEARCH DESIGN AND METHODS: Muscle blood flow (MBF) was measured with the 133Xe clearance technique in 15 nondiabetic subjects, 10 patients with insulin-dependent diabetes mellitus (IDDM), and 11 patients with non-insulin-dependent diabetes (NIDDM) at rest and after exercise. None of the patients had neuropathy. RESULTS: The median resting MBF was similar in all three groups. The median postexercise MBF was significantly greater in nondiabetic subjects (40.1 ml.min-1.100 g-1 of tissue) than in patients with IDDM (25.7 ml.min-1.100 g-1 of tissue; P less than 0.01) or NIDDM (14 ml.min-1.100 g-1 of tissue; P less than 0.01). The difference between IDDM and NIDDM was not significant. CONCLUSIONS: Diabetic patients have abnormalities of MBF in response to exercise. This abnormality occurs in the absence of clinical diabetic neuropathy.