Managing diabetes after myocardial infarction.
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Diabetes Complications↗
Biomedical subjects
M Nattrass
Publications and source records attributed to M Nattrass.
Insulin resistance: a multifaceted metabolic syndrome. Insights gained using a low-dose insulin infusion technique.
The term 'insulin resistance', when applied to human disease, is often equated with impaired whole-body insulin-mediated glucose disposal as determined using techniques such as the hyperinsulinaemic glucose 'clamp' technique. Insulin resistance may be defined in more generic terms as 'a state in which normal concentrations of insulin produce an attenuated biological response'--a definition which does not restrict consideration of insulin action to a solitary aspect of metabolism and emphasizes the importance of examining the effects of insulin at concentrations which are relevant to normal physiology. While a number of useful investigative techniques have been developed for the assessment of insulin action in man, most focus narrowly on glucose metabolism; other key aspects of metabolism have received far less attention. Moreover, the pharmacological hyperinsulinaemia usually attained during euglycaemic clamp studies is unsuitable for assessing processes such as adipocyte lipolysis which are maximally inhibited by insulin concentrations within the low-physiological range. In this article we present a summary of our investigations of insulin action in vivo using a low-dose incremental insulin infusion technique. This technique permits examination of circulating insulin/metabolite dose-response relationships within the lower physiological range of plasma insulin concentrations. Using this approach, we have identified multiple abnormalities in the regulation of carbohydrate and lipid metabolism in subjects with a diverse array of insulin-resistant states characterized by variable degrees of glucose intolerance. Of note are the consistent observations of defective regulation of non-esterified fatty acid and glycerol metabolism, being apparent even in patients in whom glucose tolerance was either normal or only marginally impaired. Our studies indicate that defective insulin action is not confined to impaired glucose disposal in insulin-resistant disorders and is usually evident in other aspects of intermediary metabolism. We suggest that the concept of insulin resistance as a pathological entity would be usefully enhanced by greater recognition of the multiple defects in insulin action which may be encountered in insulin-resistant states.
Adult↗
Diabetes care in South Asian and white European patients with type 2 diabetes.
Aspects of diabetes care in South Asian and white European patients with Type 2 diabetes attending a hospital review clinic were explored. Among the clinic population of 1710 patients, 258 (15%) were of South Asian origin. A significantly greater proportion (95% CI for difference in proportions 8-22%) of these patients was treated with oral hypoglycaemic drugs than in white Europeans, in whom there was a correspondingly greater proportion receiving insulin treatment. In a case-control study, where 154 patients in each racial group were stratified according to treatment regimen, significantly more South Asian patients (13/30 vs 6/30, p < 0.05) on insulin were treated with a once-daily regimen. Despite these observed differences in treatment of diabetes, glycaemic control was no worse in South Asian patients when compared to their white European counterparts. South Asian diabetic patients attending hospital diabetes clinics in the UK can experience similar levels of glycaemic control to white Europeans.
Asia↗
Organized chaos? Computed tomographic evaluation of the neuropathic diabetic foot.
Accurate radiographic evaluation of diabetic neuroarthropathy is increasingly difficult as the disease becomes more florid. 22 patients with a known diabetic neuroarthropathy of one or both feet were prospectively examined by computed tomography (CT) in the axial and coronal planes. Bilateral changes of a neuroarthropathy were present in 75% of cases. Distinct patterns of disease were seen and categorized into five types in order of increasing severity. Changes at the medial tarsometatarsal joints and adjacent intercuneiform joints were seen in all affected feet. More extensive disease involved the medial arch more commonly than the lateral. Fractures of the tarsal bones were found in 32% of cases and were associated with neuroarthropathic changes in adjacent joints. Calcaneal fractures were seen in four feet. A Lisfranc fracture-dislocation was present in 41% of cases and a bilateral in only 21%. A single CT examination of the foot, while an accurate method of demonstrating the extent of the disease, is an insensitive indicator of disease activity.
Adult↗
Tacrolimus (FK506) versus cyclosporin in prevention of liver allograft rejection.
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Cyclosporine↗
Postoperative glucose metabolism in liver transplant recipients. A two-year prospective randomized study of cyclosporine versus FK506.
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Adult↗
Acute myocardial infarction in diabetic patients in the thrombolytic era.
To examine the benefits of thrombolytic therapy in diabetic patients with acute myocardial infarction a retrospective study of all diabetic and non-diabetic patients with acute myocardial infarction admitted to the coronary care unit of the General Hospital, Birmingham between January 1984 and December 1987 was made and findings compared to corresponding groups admitted between January 1990 and May 1992 when thrombolytic therapy was routine. In-hospital mortality and morbidity were assessed in 208 diabetic and 1029 non-diabetic patients with acute myocardial infarction admitted 1984 and 1987 and in 115 diabetic and 501 non-diabetic patients with myocardial infarction between January 1990 and May 1992. Following the introduction of thrombolytic therapy, there was a reduction in mortality among non-diabetic patients from 17% to 8.5%; p < 0.001 (observed reduction: 49%; 95% CI: 30-70%) and in the incidence of left ventricular failure (from 22% to 8%, p < 0.1 (observed reduction: 52%; 95% CI: 40-85.5%). Diabetic patients showed a reduction in mortality from 30% to 17%; p = 0.02 (observed reduction: 42%; 95% CI: 9.4-73.8%) and in the incidence of left ventricular failure from 39% to 21%; p < 0.01 (observed reduction: 45%; 95% CI: 20.3-72.5%). Thrombolytic therapy confers a major benefit on diabetic patients with acute myocardial infarction, although this group remains at a prognostic disadvantage compared to non-diabetic patients.
Blood Glucose↗
Serum lipids and apolipoproteins in liver transplant recipients: a comparative study of cyclosporin A and FK 506.
The immunosuppressive agent cyclosporin A (CsA) is reportedly associated with clinically adverse effects on circulating lipid and apolipoprotein concentrations. To date few data have been reported concerning the effects on lipid metabolism of the new macrolide immunosuppressive agent FK 506, and no comparative studies of the effects of these drugs have been performed. In consideration of the pivotal role of the liver in lipid metabolism, we measured fasting serum lipids and apolipoproteins a median of 8 (range 5 to 9) months after the operation in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with CsA +/- azathioprine (n = 10) or FK 506 (n = 10). To avoid the confounding effects of corticosteroids on lipid metabolism, prednisolone was withdrawn at least 6 weeks beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Serum total cholesterol concentration was significantly lower in both the CsA (p < 0.001) and FK 506 (p < 0.05) treatment groups when compared with the healthy control subjects. Serum high-density lipoprotein (HDL) cholesterol concentration was also significantly lower in both the CsA (p < 0.005) and FK 506 (p < 0.01) treatment groups. Neither the ratio of serum total cholesterol to HDL cholesterol nor the fasting triglyceride concentrations were significantly different (p > 0.1) from those of the healthy control subjects for either transplant group. Serum apolipoprotein B level was lower than that of the control group in both the CsA (p < 0.005) and FK 506 groups (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoproteins↗
Euglycaemic diabetic ketoacidosis: does it exist?
The original criteria described for euglycaemic ketoacidosis (initial blood glucose less than 16.7 mmol/l and plasma bicarbonate equal to or less than 10 mmol/l) were identified in 23 of 722 consecutive episodes (3.2%) of diabetic ketoacidosis. True euglycaemic ketoacidosis (initial blood glucose 10 mmol/l or less) was rare, occurring in 0.8-1.1% of all episodes depending on the defining plasma bicarbonate concentration. Management of euglycaemic ketoacidosis with low-dose continuous intravenous infusion of insulin together with adequate fluid replacement was effective. The clinical and biochemical data did not support the concept of euglycaemic ketoacidosis as a separate entity. The importance of ketone testing rather than glucose testing in the diagnosis of ketoacidosis is, however, emphasized. The importance of adequate insulin and fluid therapy in those few episodes where blood glucose is normal or near normal at presentation is also highlighted.
Bicarbonates↗
Insulin resistance in the regulation of lipolysis and ketone body metabolism in non-insulin dependent diabetes is apparent at very low insulin concentrations.
The insulin sensitivity of intermediary metabolism was studied in 8 non-obese men with well-controlled diet-treated non-insulin dependent diabetes (NIDDM) using a low dose incremental insulin infusion (basal, 0.005 and 0.01 U/kg h-1). Results were compared to 8 healthy male control subjects matched (NIDDM vs. controls, mean +/- S.E.M.) for age (56 +/- 3 vs. 54 +/- 3 years, NS) and body mass index (24.6 +/- 0.7 vs. 25.3 +/- 0.5 kg/m2, NS). Basal fasting concentrations of insulin (4.7 +/- 0.8 vs. 3.2 +/- 0.8 mU/l, NS), glucose, total ketone bodies (TKB), and non-esterified fatty acids (NEFA) were not significantly different between the groups but glycerol concentrations were significantly elevated in NIDDM patients (0.072 +/- 0.007 vs. 0.049 +/- 0.003 mmol/l, P < 0.05). During incremental insulin infusion, plasma insulin concentrations rose to 12.8 +/- 1.5 vs. 10.0 +/- 1.0 mU/l in NIDDM patients vs. control and metabolite concentrations fell significantly (P < 0.001). Significant linear dose-response relationships were found between plasma insulin (log) and glucose, TKB (log), NEFA, and glycerol concentrations by analysis of variance applied to regression (all P < 0.001). For glucose and TKB (log), the group regression lines were parallel but were significantly right-shifted in the NIDDM group (P < 0.001). In contrast, the relationships of insulin (log) and both glycerol and NEFA concentrations converged over the observed range of insulin concentrations. Significant displacement of glycerol and NEFA dose-response relationships were found in NIDDM patients at an insulin concentration of 5 mU/l (P < 0.001) but not at 12.5 mU/l.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Hyperproinsulinaemia in impaired glucose tolerance.
1. Basal circulating concentrations of islet B cell products were measured using two-site monoclonal antibody-based immunoradiometric assays after a 10 h overnight fast in a group of non-obese subjects with recently diagnosed impaired glucose tolerance (World Health Organization criteria). A group of healthy subjects with normal oral glucose tolerance matched for age and body mass index served as normal controls. 2. Fasting blood glucose concentration was normal in all subjects with mean (+/- SEM) levels of 5.1 +/- 0.2 and 4.8 +/- 0.2 mmol/l (P > 0.1) for the group with impaired glucose tolerance and the healthy control group, respectively. 3. There was no significant difference (P > 0.1) in fasting plasma insulin or C-peptide concentrations between the groups. 4. By contrast, the fasting concentration of intact proinsulin was nearly four-fold higher in the subjects with impaired glucose tolerance than in the matched healthy control subjects (4.5 +/- 1.0 versus 1.2 +/- 0.2 pmol/l, P < 0.005). 5. Similarly, the fasting plasma concentration of 32-33 split proinsulin in the subjects with impaired glucose tolerance was almost twice that of the control subjects (7.4 +/- 1.3 versus 3.9 +/- 0.8 pmol/l, P < 0.02). 6. In conclusion, fasting concentrations of proinsulin-like molecules are elevated in non-obese subjects with newly diagnosed impaired glucose tolerance. This observation is consistent with defective islet B cell proinsulin processing in this syndrome.
Glucose Intolerance↗
Persisting mortality in diabetic ketoacidosis.
An overall hospital mortality rate of 3.9% was found in 929 episodes of diabetic ketoacidosis treated in single centre over a 21-year period. The mortality rate in the first half of the survey (4.4%) was not significantly different from that in the second half of the survey (3.4%). Six deaths in patients under 50 years of age occurred in the first half, but only one death under 50 years occurred in the second half of the survey. The number of deaths from a metabolic cause where no other illness was identified also fell from nine (43% of deaths) in the first half to five (33% of deaths) in the second half of the study (not significant). The remaining deaths were due to concurrent illness, mainly myocardial infarction and serious infections. Many of the residual deaths occurred in elderly patients with such medical illness in addition to the ketoacidosis. It may, therefore, prove difficult to reduce mortality further in diabetic ketoacidosis.
Age Factors↗
Effects of octreotide on circulating islet B cell products in endogenous hyperinsulinism.
The role of somatostatin analogues in the medical management of insulinomas is unclear. We describe an elderly patient with clinical and biochemical features of endogenous hyperinsulinism attributable to a benign islet B cell disorder whose incapacitating neuroglycopaenic symptoms responded dramatically to octreotide 50 micrograms subcutaneously at 2200 h each night. Octreotide suppressed inappropriate plasma concentrations of insulin thereby preventing fasting hypoglycaemia. Fasting concentrations of proinsulin, and 32-33 split proinsulin, as determined by two-site monoclonal antibody-based immunoradiometric assays, were also suppressed by octreotide.
Aged↗
Insulin and proinsulin-like molecules in motor neurone disease.
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Fasting↗
Metabolic effects of cyclosporin A and FK 506 in liver transplant recipients.
Postoperative diabetes is a reported feature of the immunosuppressive agents cyclosporin A and FK 506. To date, however, no randomized comparative studies of the metabolic effects of these two drugs have been performed. In this study, extended (300 min) oral glucose tolerance tests (75 g) were performed a median of 8 mo (range 5-9 mo) postoperatively in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with either cyclosporin A (with or without azathioprine) or FK 506. None of the patients had clinically overt diabetes antedating transplantation. To avoid the confounding effects of corticosteroids, prednisolone was withdrawn at least 6 wk beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Overall blood glucose concentrations after the glucose challenge were significantly elevated in both groups of transplant recipients (P < 0.005 and P < 0.001 for cyclosporin A and FK 506 treatment groups, respectively) compared with the healthy control subjects. Venous whole-blood glucose concentration (mean +/- SE) 120 min after the ingestion of oral glucose was significantly higher in both the cyclosporin A (P < 0.05) and FK 506 (P < 0.01) treatment groups compared with the control subjects (6.6 +/- 0.5 vs. 8.8 +/- 0.9 vs. 5.2 +/- 0.2 mM, respectively). According to 1985 WHO criteria, 4 of 10 cyclosporin A-treated patients had impaired glucose tolerance, whereas 3 of 10 FK 506-treated patients had diabetes with 4 others having impaired glucose tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)
Analysis of Variance↗
Hyperproinsulinaemia in patients with myotonic dystrophy.
Hyperinsulinaemia is a reported feature of the inherited multisystem disorder myotonic dystrophy. This phenomenon has been attributed to a compensatory beta cell response to tissue insulin resistance. In this study, circulating concentrations of insulin, proinsulin, and split proinsulin molecules were determined after an overnight fast in ten patients with myotonic dystrophy using two-site monoclonal antibody-based immunoradiometric assays. Results were compared with ten healthy control subjects matched for age, gender, and body mass index. Oral glucose tolerance (75 g), as defined by World Health Organization criteria, was normal in all subjects. Fasting plasma immunoreactive insulin concentration, as determined using a conventional radioimmunoassay, was almost three times higher (p < 0.005) in the myotonic dystrophy patients than the healthy control subjects. By contrast, fasting concentrations (mean +/- SEM) of C-peptide (0.75 +/- 0.09 vs 0.52 +/- 0.03 nmol/l, p = 0.07) and immunoradiometrically-determined insulin (60 +/- 12 vs 38 +/- 4 pmol/l, p = 0.09) were not significantly different between the groups. Fasting concentrations of proinsulin (10.3 +/- 2.9 vs 1.6 +/- 0.3 pmol/l, p < 0.01), and 32-33 split proinsulin (7.8 +/- 2.5 vs 2.9 +/- 0.4 pmol/l, p < 0.05) were significantly elevated in the patients with myotonic dystrophy. Accordingly, the mean fasting proinsulin:insulin ratio, expressed as a percentage, was significantly increased in the myotonic patients (20 +/- 5 vs 4 +/- 1%, p < 0.01). The overall C-peptide response to the oral glucose challenge was significantly greater in the myotonic patients compared with the healthy control subjects (p < 0.001). These results provide corroborative evidence of increased beta-cell secretion in myotonic dystrophy.(ABSTRACT TRUNCATED AT 250 WORDS)
C-Peptide↗
Effects of morbid obesity on insulin clearance and insulin sensitivity in several aspects of metabolism as assessed by low-dose insulin infusion.
Obesity is associated with impaired insulin action in glucose disposal, but not necessarily in other aspects of intermediary metabolism or insulin clearance. Sixteen morbidly obese and 14 normal-weight subjects (body mass index, 51.2 +/- 11.5 v 22.1 +/- 2.2 kg.m-2; mean +/- SD) were studied with sequential, low-dose, incremental insulin infusion with estimation of glucose turnover. In obese patients, basal plasma insulin was higher (10.5 +/- 3.8 v 2.4 +/- 3.0 mU.L-1, P less than .001) and remained elevated throughout infusion (F = 492, P less than .001), as did C-peptide (F = 22.7, P less than .001). Metabolic clearance rate for insulin (MCRI) at the highest infusion rate was similar (1,048 +/- 425 v 1,018 +/- 357 mL.m-2.min-1, NS). Basal hepatic glucose production in obese subjects was less than in normal-weight subjects (270 +/- 108 v 444 +/- 68 mumol.m-2.min-1, P less than .01), as was the basal metabolic clearance rate for glucose (MCRG, 77 +/- 26 v 108 +/- 31 mL.m-2.min-1, P less than .05). Insulin infusion caused blood glucose to decrease less in the obese patients (1.4 +/- 0.5 v 1.9 +/- 0.5 mmol.L-1, P less than .05); hepatic glucose production was appropriately suppressed in them by hyperinsulinemia, but their insulin-mediated glucose disposal was reduced (1.67 [0.79] v 4.45 [2.13] mL.m-2.min-1/mU.L-1, P less than .01). Concentrations of nonesterified fatty acids (NEFA), glycerol, and ketones were elevated throughout the insulin infusions in obese patients, despite the higher insulin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Metabolic effects of monomeric insulin analogues of different receptor affinity.
The effects of two monomeric insulin analogues of differing receptor affinities (human insulin = 100%) B9Asp-B27Glu-insulin (18%) and B10Asp-insulin (327%) were each compared with human insulin in two groups of 10 normal men when infused at equimolar low doses (1.0 and 2.0 pmol kg-1 min-1). The metabolic clearance rate under steady state conditions was highest for the analogue with the highest receptor affinity, 26.8 +/- 0.8 (+/- SE) vs 19.8 +/- 0.7 ml kg-1 min-1 for insulin (p less than 0.001), and lowest for the analogue with the lowest receptor affinity, 13.3 +/- 0.8 vs 25.1 +/- 2.0 ml kg-1 min-1 for insulin (p less than 0.001). The apparent plasma half-life was prolonged for the low affinity analogue compared with human insulin (12.6 +/- 0.6 vs 1.9 +/- 0.2 min, p less than 0.001), and significantly shorter for the higher affinity analogue (1.6 +/- 0.1 vs 3.1 +/- 0.4 min, p less than 0.05). The three insulins gave similar falls in blood glucose, non-esterified fatty acids, glycerol, and total ketone bodies over the infusion period. Thirty minutes after the end of the infusion, the rise in blood glucose for the low affinity analogue was significantly less than for human insulin (0.5 +/- 0.2 vs 0.9 +/- 0.1 mmol l-1, p less than 0.05). Despite different receptor affinities, these analogues have similar in vivo effects in normal men, but the time-course of their actions may differ when they are infused intravenously.
Adult↗