Which is the eligible patient to be treated with pioglitazone? The expert view.

Pioglitazone has an important role in the treatment of patients with Type 2 diabetes. The drug can help patients to achieve sustained glycemic control and may delay the requirement for insulin. Pioglitazone may provide benefits beyond its effects on glycemia, with data suggesting it may confer anti-atherosclerotic and cardioprotective properties. Attention should be given to possible side effects relating to class effects of TZD, and selection of appropriate patients to be prescribed pioglitazone will enable optimum benefits to be derived from pioglitazone treatment.

Comparing the actions of older and newer therapies on body weight: to what extent should these effects guide the selection of antidiabetic therapy?

BACKGROUND: Type 2 diabetes patients are usually overweight or obese. Further weight gain induced by antidiabetic treatment should be avoided if possible. Much attention has been focussed recently on the potential for GLP-1 mimetics, in particular, to reduce weight. AIMS: Effects on weight are but one of several important criteria in selecting antidiabetic therapy, however. This review explores the effects on weight of older classes of antidiabetic agents (metformin, sulfonylureas, thiazolidinediones) and the newer drugs acting via the GLP-1 system. Other aspects of their therapeutic profiles and current therapeutic use are reviewed briefly to place effects on weight within a broader context. FINDINGS: Comparative trials demonstrated weight neutrality or weight reduction with metformin, and weight increases with a sulfonylurea or thiazolidinedione. There was no clinically significant change in weight with DPP-4 inhibitors and a small and variable decrease in weight (about 3 kg or less) with GLP-1 mimetics. Improved clinical outcomes have been demonstrated for metformin and a sulfonylurea (cardiovascular and microvascular benefits, respectively, in the UK Prospective Diabetes Study), and secondary endpoints improved modestly with pioglitazone in the PROactive trial. No outcome benefits have been demonstrated to date with GLP-1-based therapies, and these agents exert little effect on cardiovascular risk factors. Concerns remain over long-term safety of these agents and this must be weighed against any potential benefit on weight management. CONCLUSIONS: Considering effects on weight within the overall risk-benefit profile of antidiabetic therapies, metformin continues to justify its place at the head of current management algorithms for type 2 diabetes, due to its decades-long clinical evidence base, cardiovascular outcome benefits and low cost.

The Clinical Significance of PPAR Gamma Agonism.

Insulin resistance is a principal underlying defect in type 2 DM along with beta-cell dysfunction, and this insulin resistance underpins many of the abnormalities associated with the metabolic syndrome. Peroxisome-proliferator-activated receptor gamma agonists (PPARgamma agonists), also known as glitazones or thiazolidinediones (TZDs) are powerful insulin sensitisers with recent evidence suggesting that they also have a potential to improve pancreatic beta-cell function. TZDs cause a major redistribution of body fat with a decrease in visceral and hepatic fat content with a resultant increase in insulin sensitivity. The glucose lowering effects of TZDs are similar to those seen with the well-established sulphonylureas and metformin. TZDs have a small reducing effect on blood pressure and have been shown to reduce microalbuminuria independent of their blood glucose lowering effect. Both TZDs in clinical practice, pioglitazone and rosiglitazone, reduce small dense LDL-cholesterol and increase HDL-cholesterol levels but pioglitazone would appear to have a more pronounced benefit on these two parameters with a greater reduction in plasma triglycerides. TZDs improved the pro-coagulant state and show benefits in improving endothelial dysfunction and reducing 'non-traditional' inflammatory cytokines and increasing adiponectin levels. The greatest benefit for the TZDs is to directly influence atherogenesis itself and the potential that these so-called pleiotrophic effects of TZDs to reduce cardiovascular events in type 2 DM will be tested when the results of outcome trials are published in the next few years. If the results are positive for the reduction in vascular end-points, then TZDs will represent a major advance in improving the prognosis of type 2 DM subjects with the metabolic syndrome.

9-Alpha-fluorohydrocortisone in the treatment of postural hypotension in diabetic autonomic neuropathy.

A double-blind crossover study of fludrocortisone, 0,1 mg. twice daily, and placebo is reported in six diabetics with troublesome symptoms of postural hypotension due to autonomic neuropathy. During treatment with the active preparation there was an increase in the lying and tilted systolic blood pressure, a decrease in orthostatic tachycardia, and in increase in the total plasma volume and body weight, but with no change in plasma or urine osmolality; The symptoms of postural hypotension improved in four patients, while two patients with a low serum albumin developed ankle edema during treatment with fludrocortisone. It is concluded that fludrocortisone is effective in diabetics with symptomatic postural hypotesnion, but should be used with caution in patients with a low serum albumin.

Mononeuropathy in diabetes mellitus.

Fifty-one diabetic patients with mononeuropathies wereoneuropathy were studied to examine possible etiological factors, to determine the relationship with other diabetic complications, and to correlate with the presence and severity of background peripheral and autonomic neuropathy. The median, ulnar, and lateral popliteal nerves were most commonly affected and cranial neuropathy was relatively uncommon. When bilateral involvement of the same nerve was excluded, multiple mononeuropathies were found in only five patients. Median and ulnar mononeuropathy were gradual in onset and affected the dominant limb whereas other types of mononeuropathies were acute in onset with no predilection for either side. No consistent relationship was shown between the onset of mononeuropathy and age, sex, diabetic treatment, duration of diabetes, diabetic control, or other diabetic complications. In particular, there was no significant background peripheral and autonomic neuropathy, as assessed clinically and by objective tests, in almost one-half of the patients studied. It is concluded that diabetic mononeuropathy may occur independently of peripheral and autonomic neuropathy. It is possible, however, that a minimal degree of background damage, known to be present in all diabetic patients, may render them more susceptible than the general population to the various factors causing mononeuropathy.

Peripheral and autonomic nerve function in newly diagnosed diabetes mellitus.

Peripheral and autonomic nerve function was assessed in 10 newly diagnosed male diabetics (six insulin-treated and four sulfonylurea-treated) with repeated observations over the subsequent six months. There was significant impairment of motor-conduction velocity in the common peroneal nerve at diagnosis in both treatment groups, with improvement following treatment in only the insulin-treated patients. In contrast, although the blood glucose level fell in both groups, the mean level was significantly lower in the sulfonylurea-treated patients at two months and at each subsequent visit. In the autonomic function tests significant abnormality was found in the electrocardiographic R-R-interval (beat-to-beat) variation in resting heart rate in two of the insulin-treated patients and all of the sulfonylurea-treated group, with improvement in only one of the latter. One patient in the sulfonylurea-treated group also showed an abnormal response to the Valsalva maneuver (expressed as the Valsalva ratio), and this remained abnormal throughout the period of study. All other patients had normal responses to the Valsalva maneuver and sustained handgrip test. None of the patients had postural hypotension. Abnormalities in autonomic nerve function in diabetics at diagnosis have not been previously reported.

Plasma beta-thromboglobulin in diabetes mellitus.

The plasma beta-thromboglobulin (betaTG) content was measured in 56 diabetic patients with known complications of this disease, including neuropathy, retinopathy, and ischemic skin lesions. Although two patients were found to have elevated levels beyond the normal range, there was no significant difference between the diabetic group as a whole and the group of 35 controls. The significance of these findings with regard to the proposed contribution of small-vessel platelet sequestration in the pathogenesis of late complications of diabetes mellitus is discussed.

Growth factor-induced stimulation of hexose transport in 3T3-L1 adipocytes: evidence that insulin-induced translocation of GLUT4 is independent of activation of MAP kinase.

We have examined the effect of growth factors on the rate of hexose transport in 3T3-L1 adipocytes. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) were found to stimulate deoxyglucose transport by about 2-fold. The concentrations of EGF and PDGF which elicited half maximal responses were 100 and 350 pM, respectively. The increases in transport rate were acute effects; the stimulations were evident within minutes of exposure to growth factors. By contrast, insulin stimulated deoxyglucose transport approximately 16-fold over similar time periods. We have measured the appearance of both the insulin-responsive glucose transporter (GLUT4) and the erythrocyte-type glucose transporter (GLUT1) at the cell surface in response to insulin, EGF and PDGF. We show that both EGF and PDGF induce a 2-fold increase in GLUT1 at the cell surface, but both these growth factors were without effect on GLUT4 levels at the cell surface. In contrast, insulin induced a 13-fold increase in cell surface GLUT4. We further show that insulin, EGF and PDGF all activate MAP kinase as determined by a shift in electrophoretic mobility of this protein on SDS-PAGE. However, since the large translocation of GLUT4 to the cell surface is specific for insulin, we suggest that activation of MAP kinase is not the sole requisite for this process.

Severe amnesia after hypoglycemia. Clinical, psychometric, and magnetic resonance imaging correlations.

OBJECTIVE: To determine the correlation between clinical, psychometric, and magnetic resonance imaging (MRI) findings after an episode of hypoglycemic coma resulting in amnesia. RESEARCH DESIGN AND METHODS: Detailed psychometric assessment, especially memory testing, performed with MRI in a man with severe amnesia after hypoglycemic coma. RESULTS: Psychometric testing confirmed impaired immediate recall. MRI findings were consistent with a lesion in the left temporal lobe. CONCLUSIONS: This is the first description of MRI in determining the neurological damage in hypoglycemic coma.

Provocation of postural hypotension by nitroglycerin in diabetic autonomic neuropathy?

The effect of nitroglycerin on heart rate and systolic blood pressure was compared in 5 normal subjects, 12 diabetic subjects without autonomic neuropathy, and 5 diabetic subjects with autonomic neuropathy. The magnitude and time course of the increase in heart rate and the decrease in systolic blood pressure after nitroglycerin were similar in the normal and diabetic subjects without autonomic neuropathy, whereas a lesser increase in heart rate and a greater decrease in systolic blood pressure occurred in the diabetic subjects with autonomic neuropathy. It is therefore suggested that caution should be exercised when prescribing vasodilator drugs in diabetic patients, particularly those with autonomic neuropathy.

Effect of alcohol intake on symptomatic peripheral neuropathy in diabetic men.

In a group of 541 white diabetic men aged 20--59 yr attending one clinic it was found that 91 (15%) drank heavily, while a further 39 (7%) had frank alcoholism. The prevalence of symptomatic peripheral neuropathy was much higher in the 120 men who drank excessively. It is considered important, therefore, when treating diabetic patients with peripheral neuropathy not to assume that the diabetes itself is the cause in all cases. The alcoholic intake of the patient should be ascertained and, if excessive, it should be pointed out to the patient that this may well be the predominant factor causing symptoms.

Small muscle wasting of the hands in diabetes mellitus.

The clinical features and peripheral somatic and autonomic nerve function were studied in 10 diabetic subjects (nine men, one woman; mean age 59 yr, range 41-68 yr; mean duration of diabetes 20 yr, range 8 mo to 33 yr) with generalized small muscle wasting of the hands. Five patients were insulin-dependent and five non-insulin-dependent. Nine had retinopathy (two proliferative, seven background), five nephropathy, two ischemic heart disease, and seven peripheral vascular disease. Nine patients had clinical evidence of sensory peripheral neuropathy and absent reflexes in the lower limbs. Eight patients had distal sensory impairment and/or absent reflexes in the upper limbs. Seven had two or more symptoms of autonomic neuropathy. Nerve conduction measurements in the median, ulnar, and lateral popliteal nerves showed that all patients had moderate to severe polyneuropathy affecting both motor and sensory fibers. Nine had one or more abnormal cardiovascular autonomic function tests. Electromyography of affected muscles in the hands showed changes of chronic partial denervation and collateral reinnervation in all cases.

Use of GPI-anchored proteins to study biomolecular interactions by surface plasmon resonance.

Surface plasmon resonance is a powerful tool to examine the kinetics of cell surface receptor-ligand interactions and requires only small amounts of protein. For these studies, one component is required in highly purified form to be coupled to the biosensor surface. The second component does not need to be purified. The human high affinity receptor for immunoglobulin G, FcgammaRI, presents a problem as the receptor itself cannot readily be produced in large amounts for purification and, as there are eight potential ligands for the receptor (human IgG1-4 and mouse IgG1, 2a, 2b and 3), it is difficult to immobilise the ligand. Using a previously established method for generating GPI-anchored proteins, we have produced and captured a soluble version of FcgammaRI and shown that it retains its affinity for human IgG1 and specificity for the different IgG subclasses. In addition, we also produced and captured a GPI-anchored version of the cell adhesion molecule CD2. This system circumvents the need for extensive receptor purification and is very rapid as solubilised receptors can be transferred from the cell surface to the sensor chip in 2 h. This system may be generally applicable for biosensor studies to other type I membrane proteins, and/or naturally occurring GPI-anchored proteins, especially where the interaction between a ligand and a panel of variant receptors is to be studied.

Overlap of IGF- and heparin-binding sites in rat IGF-binding protein-5.

Using site-directed mutagenesis, we have undertaken a study of a potential IGF-binding site in the C-terminal domain of rat IGFBP-5, lying close to or within a previously described heparin-binding domain (residues 201-218) in this protein. After analysis of binding activity using three different methods - ligand blotting, solution phase equilibrium binding and biosensor measurement of real-time on- and off-rates - we report that the mutation of two highly conserved residues within this region (glycine 203 and glutamine 209) reduces the affinity of the binding protein for both IGF-I and IGF-II, while having no effect on heparin binding. In addition, we confirm that mutation of basic residues within the heparin-binding domain (R201L, K202E, K206Q and R214A) results in a protein that has attenuated heparin binding but shows only a small reduction in affinity for IGF-I and -II. Previous findings have described the reduction in affinity of IGFBP-5 for IGFs that occurs after complexation of the binding protein with heparin or other components of the extracellular matrix (ECM) and have postulated that such an interaction may result in conformational changes in protein structure, affecting subsequent IGF interaction. Our data suggesting potential overlap of heparin- and IGF-binding domains argue for a more direct effect of ECM modulation of the affinity of IGFBP-5 for ligand by partial occlusion of the IGF-binding site after interaction with ECM.

Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus?

Results from the United Kingdom Prospective Diabetes Study showed that intensive treatment of type 2 (non-insulin-dependent) diabetes mellitus, with sulphonylureas or insulin, significantly reduced microvascular complications but did not have a significant effect on macrovascular complications after 10 years. Insulin resistance plays a key role in type 2 diabetes mellitus and is linked to a cluster of cardiovascular risk factors. Optimal treatment for type 2 diabetes mellitus should aim to improve insulin resistance and the associated cardiovascular risk factors in addition to achieving glycaemic control. Treatment with sulphonylureas or exogenous insulin improves glycaemic control by increasing insulin supplies rather than reducing insulin resistance. Metformin and the recently introduced thiazolidinediones have beneficial effects on reducing insulin resistance as well as providing glycaemic control. There is evidence that, like metformin, thiazolidinediones also improve cardiovascular risk factors such as dyslipidaemia and fibrinolysis. Whether these differences will translate into clinical benefit remains to be seen. The thiazolidinediones rosiglitazone and pioglitazone have been available in the US since 1999 (with pioglitazone also being available in Japan). Both products are now available to physicians in Europe.

Effects of improved glycaemic control on calcium and magnesium homeostasis in type II diabetes.

Poorly controlled type II diabetic patients with hypomagnesaemia, hypermagnesuria, and hypercalciuria were allocated to treatment with either metformin or glipizide, to determine the effects on some indices of mineral metabolism. Despite comparable improvement in glycaemic control, assessed by glucose and haemoglobin A1, there were significant differences between the two groups in the handling of magnesium. Patients receiving metformin showed a reduction in magnesium excretion but remained hypomagnesaemic and hypercalciuric. In contrast, patients receiving glipizide exhibited little change in either magnesium or calcium excretion but showed a significant rise in serum magnesium.

Metformin efficacy and tolerance in obese non-insulin dependent diabetics: a comparison of two dosage schedules.

A comparative open study of metformin unit doses of 500 mg and 850 mg was carried out in 64 obese, non-insulin dependent diabetics on 1.5 to 3 g metformin daily. Glycaemic response, blood lactate, plasma metformin concentrations and tolerance for metformin were assessed. On changing from a 500 mg unit dose to an equivalent total dose of metformin using the 850 mg preparation, there were no significant changes in the random blood glucose, glycated haemoglobin, or blood lactate concentrations. Metformin plasma concentrations remained unchanged except for patients transferred from 1.5 to 2.0 g daily to 850 mg twice daily; in these patients plasma concentrations increased from 1.83 +/- 0.87 to 2.50 +/- 0.89 micrograms/l (p less than 0.01). Seven patients (3 asymptomatic and 4 with background symptoms) became intolerant of the 850 mg regimen and required to return to the 500 mg dose regimen. After exclusion of patients intolerant of the 850 mg dose regimen (11%), the remaining patients noted no significant change in symptoms and 28% of all patients transferred to the 850 mg dose unit indicated an overall preference for this regimen.

Sex difference in the relationship of calcium and magnesium excretion to glycaemic control in type 1 diabetes mellitus.

In order to assess the variability and possible causes of calcium and magnesium losses in diabetes mellitus, urinary calcium and magnesium excretion were monitored six monthly over a 3-year period in 108 stable, type 1 diabetic patients who were having assessment of their clinical status and glycaemic control over the same period. In the patients studied the ranges of excretion of both calcium and magnesium were considerably wider than our non-diabetic reference ranges but the within subject variation in excretion was high. However, using mean values obtained over the study period, a direct relationship was observed between the excretion of both calcium and magnesium and HbA1 in female patients (P < 0.01) but not in males who had similar HbA1 values. The urinary excretion of calcium and magnesium did not relate to any of the other clinical or biochemical indices measured, including body mass index, daily insulin dose, retinal status or albumin excretion. It is suggested that, in poorly controlled patients, females may have a greater risk than males of developing the complications associated with chronic calcium and magnesium loss.

Incidence of blindness due to diabetic eye disease in Fife 1990-9.

AIMS: In the light of goals for reducing blindness due to diabetes, published in the St Vincent Declaration, 1989, the aim of this study was to find the incidence and prevalence of blindness in the diabetic population of Fife. METHODS: All blind registrations for the period 1990-9 were studied. Those with diabetes as the first or main diagnosis were included as new diabetic blind. The prevalence of diabetes was studied in a large sample population and extrapolated to the estimated population of Fife. RESULTS: The incidence of blindness due to diabetes was 64 (SD 24, 95% CI 49-79) per 100 000 diabetic population/year. The point prevalence of blindness due to diabetes on 31 December 1999 was 210 per 100 000 diabetic population. CONCLUSION: The incidence of blindness due to diabetes, in a diabetic population, is now known. Without this benchmark it is impossible to assess the implementation of the St Vincent Declaration.

Hashimoto's encephalopathy presenting as an acute medical emergency.

Three cases are described of a reversible encephalopathy, all presenting with marked neurological disturbance. In all three, the diagnosis was not clear at the time of presentation but eventually it was felt all of the cases were consistent with Hashimoto's encephalopathy. The diagnosis of Hashimoto's encephalopathy should be considered in any case of unexplained encephalopathy. Common features are high anti-thyroid peroxidase antibody titres, an abnormal EEG and an elevated CSF protein concentration. The encephalopathy is independent of thyroid hormonal status. Treatment with corticosteroids leads to a prompt resolution of symptoms and long-term low dose steroid therapy prevents further neurological recurrence.