John C. Pickup

NIDDM as a disease of the innate immune system : association of acute-phase reactants and interleukin-6 with metabolic syndrome X

SummaryNon-insulin-dependent diabetes mellitus (NIDDM) is commonly associated with hypertrigly-ceridaemia, low serum HDL-cholesterol concentrations, hypertension, obesity and accelerated atherosclerosis (metabolic syndrome X). Since a similar dyslipidaemia occurs with the acute-phase response, we investigated whether elevated acute-phase/stress reactants (the innate immune system’s response to environmental stress) and their major cytokine mediator (interleukin-6, IL-6) are associated with NIDDM and syndrome X, and may thus provide a unifying pathophysiological mechanism for these conditions. Two groups of Caucasian subjects with NIDDM were studied. Those with any 4 or 5 features of syndrome X (n = 19) were compared with a group with 0 or 1 feature of syndrome X (n = 25) but similar age, sex distribution, diabetes duration, glycaemic control and diabetes treatment. Healthy non-diabetic subjects of comparable age and sex acted as controls. Overnight urinary albumin excretion rate, a risk factor for cardiovascular disease, was also assayed in subjects to assess its relationship to the acute-phase response. Serum sialic acid was confirmed as a marker of the acute-phase response since serum concentrations were significantly related to established acute-phase proteins such as α-1 acid glycoprotein (r = 0.82, p < 0.0001). There was a significant graded increase of serum sialic acid, α-1 acid glycoprotein, IL-6 and urinary albumin excretion rate amongst the three groups, with the lowest levels in non-diabetic subjects, intermediate levels in NIDDM patients without syndrome X and highest levels in NIDDM patients with syndrome X. C-reactive protein and cortisol levels were also higher in syndrome X-positive compared to -negative patients and serum amyloid A was higher in both diabetic groups than in the control group. We conclude that NIDDM is associated with an elevated acute-phase response, particularly in those with features of syndrome X. Abnormalities of the innate immune system may be a contributor to the hypertriglyceridaemia, low HDL cholesterol, hypertension, glucose intolerance, insulin resistance and accelerated atherosclerosis of NIDDM. Microalbuminuria may be a component of the acutephase response.

Is Type II diabetes mellitus a disease of the innate immune system

Summary Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, α-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acute-phase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair. [Diabetologia (1998) 41: 1241–1248]

Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes.

Type 2 diabetes is associated with increased circulating concentrations of markers of the acute-phase response and interleukin-6 (IL-6). An augmented acute-phase response may be a mechanism which explains many of the clinical and biochemical features of type 2 diabetes and its complications. We sought to confirm that circulating concentrations of the cytokine acute-phase mediators IL-6 and tumour necrosis factor alpha [TNFalpha] are elevated in type 2 diabetes, and investigated blood as a source of cytokines in type 2 diabetes. Blood samples from 20 type 2 diabetic and 17 age-matched healthy subjects were incubated in vitro for 24 hr with and without lipopolysaccharide (LPS) stimulation and secreted cytokines measured. Plasma IL-6 and TNFalpha were significantly increased in type 2 diabetes compared to normal subjects. However, basal production of IL-6 and TNFalpha in cultured diabetic blood was markedly depressed in comparison with non-diabetic samples. IL-6 and TNFalpha production was increased in blood in response to LPS, reaching similar levels in diabetic and non-diabetic subjects, though IL-6 was slightly but significantly higher in controls. We conclude that circulating levels of IL-6 and TNFalpha are increased in type 2 diabetes but there is downregulation of basal cytokine production in blood cells in type 2 diabetes. Blood has the capacity to produce cytokines in diabetes which contribute to the augmented acute-phase response, but the main source of the increased plasma IL-6 and TNFalpha concentrations may be from non-circulating cells.

Continuous subcutaneous insulin infusion: an approach to achieving normoglycaemia.

A study was performed to examine the feasibility of achieving long periods of near-normoglycaemia in patients with diabetes mellitus by giving a continuous subcutaneous infusion of insulin solution from a miniature, battery-driven, syringe pump. Twelve insulin-dependent diabetics had their insulin pumped through a subcutaneously implanted, fine nylon cannula; the basal infusion rate was electronically stepped up eightfold before meals. The blood glucose profile of these patients was closely monitored during the 24 hours of the subcutaneous infusion and compared with the profile on a control day, when the patients were managed with their usual subcutaneous insulin. Diet and exercise were standardised on both days. In five out of 14 studies the subcutaneous insulin infusion significantly lowered the mean blood glucose concentration without producing hypoglycaemic symptoms; in another six patients the mean blood glucose concentration was maintained. As assessed by the M value the level of control was statistically improved in six out of 14 studies by the infusion method and maintained in six other patients. To assess the effects of blood glucose control on diabetic microvascular disease it will be necessary to achieve long-term normoglycaemia in selected diabetics. The results of this preliminary study suggest that a continuous subcutaneous insulin infusion may be a means of maining physiological glucose concentrations in diabetics. Though several problems remain--for example, in determining the rate of infusion--longer-term studies with the miniature infusion pumps are now needed.

Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta›analysis of randomised controlled trials

Abstract Objective: To compare glycaemic control and insulin dosage in people with type 1 diabetes treated by continuous subcutaneous insulin infusion (insulin infusion pump therapy) or optimised insulin injections. Design: Meta-analysis of 12 randomised controlled trials. Participants: 301 people with type 1 diabetes allocated to insulin infusion and 299 allocated to insulin injections for between 2.5 and 24 months. Main outcome measures: Glycaemic control measured by mean blood glucose concentration and percentage of glycated haemoglobin. Total daily insulin dose. Results: Mean blood glucose concentration was lower in people receiving continuous subcutaneous insulin infusion compared with those receiving insulin injections (standardised mean difference 0.56, 95% confidence interval 0.35 to 0.77), equivalent to a difference of 1.0 mmol/l. The percentage of glycated haemoglobin was also lower in people receiving insulin infusion (0.44, 0.20 to 0.69), equivalent to a difference of 0.51%. Blood glucose concentrations were less variable during insulin infusion. This improved control during insulin infusion was achieved with an average reduction of 14% in insulin dose (difference in total daily insulin dose 0.58, 0.34 to 0.83), equivalent to 7.58 units/day. Conclusions: Glycaemic control is better during continuous subcutaneous insulin infusion compared with optimised injection therapy, and less insulin is needed to achieve this level of strict control. The difference in control between the two methods is small but should reduce the risk of microvascular complications. What is already known on this topic Continuous subcutaneous insulin infusion (insulin pump therapy) produces good long term control of blood glucose concentrations in people with type 1 diabetes Control of blood glucose concentration is substantially better on pump therapy than conventional (non-optimised) injection therapy It is unclear how glycaemic control on pump therapy compares with modern optimised insulin injection regimens What this study adds Though glycaemic control was better during continuous subcutaneous insulin infusion than optimised insulin injection therapy, the difference was relatively small Continuous subcutaneous insulin infusion is an effective form of intensive insulin therapy that should lower the risk of microvascular complications Insulin pump therapy is unnecessary for most people with type 1 diabetes and should be reserved for those with special problems with optimised insulin injections

Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta‐analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion

Aims  Continuous subcutaneous insulin infusion (CSII) is a recommended treatment for reducing severe hypoglycaemia in Type 1 diabetes, but the change in hypoglycaemia compared with multiple daily insulin injections (MDI) is unclear. We therefore conducted a meta‐analysis comparing severe hypoglycaemia and glycaemic control during CSII and MDI.

Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data

Objective To determine the clinical effectiveness of real time continuous glucose monitoring compared with self monitoring of blood glucose in type 1 diabetes. Design Meta-analysis of randomised controlled trials. Data sources Cochrane database for randomised controlled trials, Ovid Medline, Embase, Google Scholar, lists of papers supplied by manufacturers of continuous glucose monitors, and cited literature in retrieved articles. Studies reviewed Randomised controlled trials of two or more months’ duration in men and non-pregnant women with type 1 diabetes that compared real time continuous glucose monitoring with self monitoring of blood glucose and where insulin delivery was the same in both arms. Analysis Two step meta-analysis of individual patient data with the primary outcome of final glycated haemoglobin (HbA1c) percentage and area under the curve of hypoglycaemia (glucose concentration <3.9 mmol/L) during either treatment, followed by one step metaregression exploring patient level determinants of HbA1c and hypoglycaemia. Results Six trials were identified, consisting of 449 patients randomised to continuous glucose monitoring and 443 to self monitoring of blood glucose. The overall mean difference in HbA1c for continuous glucose monitoring versus self monitoring of blood glucose was −0.30% (95% confidence interval −0.43% to −0.17%) (−3.0, −4.3 to −1.7 mmol/mol). A best fit regression model of determinants of final HbA1c showed that for every one day increase of sensor usage per week the effect of continuous glucose monitoring versus self monitoring of blood glucose increased by 0.150% (95% credibility interval −0.194% to −0.106%) (1.5, −1.9 to −1.1 mmol/mol) and every 1% (10 mmol/mol) increase in baseline HbA1c increased the effect by 0.126% (−0.257% to 0.0007%) (1.3, −2.6 to 0.0 mmol/mol). The model estimates that, for example, a patient using the sensor continuously would experience a reduction in HbA1c of about 0.9% (9 mmol/mol) when the baseline HbA1c is 10% (86 mmol/mol). The overall reduction in area under the curve of hypoglycaemia was −0.28 (−0.46 to −0.09), corresponding to a reduction in median exposure to hypoglycaemia of 23% for continuous glucose monitoring compared with self monitoring of blood glucose. In a best fit regression model, baseline area under the curve of hypoglycaemia was only weakly related to the effect of continuous glucose monitoring compared with self monitoring of blood glucose on hypoglycaemia outcome, and sensor usage was unrelated to hypoglycaemia at outcome. Conclusions Continuous glucose monitoring was associated with a significant reduction in HbA1c percentage, which was greatest in those with the highest HbA1c at baseline and who most frequently used the sensors. Exposure to hypoglycaemia was also reduced during continuous glucose monitoring. The most cost effective or appropriate use of continuous glucose monitoring is likely to be when targeted at people with type 1 diabetes who have continued poor control during intensified insulin therapy and who frequently use continuous glucose monitoring.

In vivo molecular sensing in diabetes mellitus: an implantable glucose sensor with direct electron transfer

SummaryMiniature, amperometric glucose sensors were constructed for implantation in the subcutaneous tissue of normal and insulin-dependent diabetic subjects. To minimise dependence on fluctuating tissue oxygen tension, we employed the technology of mediated electron transfer, with 1,1′-dimethylferrocene acting as the redox shuttle between immobilized glucose oxidase and a platinum base electrode. In 6 normal subjects, the subcutaneous sensor responses mirrored the simultaneously-measured changes in blood glucose concentration after a 75 g oral glucose load and after intravenous injection of 0.15 U/kg short-acting insulin, though increases and decreases in the sensor output were slower than the glycaemic changes. The mean peak delay in sensor response after the oral glucose was 40 min (range 0–45 min) and the delay in the hypoglycaemic nadir was 4 min (range 0–15 min). In 5 insulin-dependent diabetic subjects, spontaneous and induced hypoglycaemia was detectable by the implanted sensor. In addition, marked and frequent oscillations in the sensor current occurred in several normal and diabetic individuals as the blood glucose fell below about 1.9 mmol/l. These oscillations were present in a diabetic subject who had lost adrenergic warning symptoms to hypoglycaemia. Continuous metabolic monitoring in diabetes, particularly the detection of hypoglycaemia, may be possible with implanted sensors based on this technology.

Effect of Control of Blood Glucose on Urinary Excretion of Albumin and β2 Microglobulin in Insulin-Dependent Diabetes

To study the effects of improved control of blood glucose on markers of renal glomerular and tubular function, we initially determined, by radioimmunoassay technics, urinary excretion rates of albumin and beta2 microglobulin in 17 nondiabetic subjects and in 43 insulin-dependent, clinically nonproteinuric diabetic patients. Duration of diabetes ranged from six months to 39 years, and the patients were studied while receiving conventional therapy. Mean urinary albumin excretion was significantly elevated in the diabetics, but beta2-microglobulin excretion rates were not different from those of the controls, suggesting that the increased albumin excretion was due to increased transglomerular loss of albumin. Seven patients with long-term diabetes (duration of six to 33 years), selected because of elevated albumin excretion, were studied before and during a continuous, subcutaneous insulin infusion for a period of one to three days. Urinary albumin excretion was significantly reduced during the insulin infusion, but mean beta2-microglobulin excretion did not change. Strict control of blood glucose, even in the short term, may reverse a functional renal abnormality in long-duration, insulin-dependent diabetes.

In vitro testing of a simply constructed, highly stable glucose sensor suitable for implantation in diabetic patients

We have constructed and tested in vitro a potentially implantable, needle-type amperometric enzyme electrode which is suitable for continuous monitoring of glucose concentrations in diabetic patients. The major requirements of stability during operation and ease of manufacture have been met with a sensor design which involves a simple dip-coating procedure for applying to a platinum base electrode an inner membrane of glucose oxidase immobilised in polyhydroxyethyl methacrylate (pHEMA), and an outer membrane composed of a pHEMA/polyurethane mixture. Sensors were operated at 700 mV for detection of hydrogen peroxide. Calibration curves for the sensor were linear to at least 20 mM glucose and were unaffected by a reduction in PO2 from 20 to 5 kPa. During continuous operation in 5 mM buffered glucose solutions in vitro, sensors suffered no significant loss of response over periods of up to 60 h. Such electrodes are, therefore, useful for development as in vivo glucose sensors.