Stephen G. Gilbey

Impact of Type 2 Diabetes Mellitus on Sympathetic Neural Mechanisms in Hypertension

Background—Essential hypertension (EHT) is a major cardiovascular risk factor, and the additional presence of type 2 diabetes mellitus (DM2) increases this risk. However, although the sympathetic nerve hyperactivity of EHT is known to play a role in cardiovascular risk, the level of sympathetic nerve activity is known neither in DM2 nor in hypertensive type 2 diabetic patients (EHT+DM2). Therefore, we planned to quantify the vasoconstrictor sympathetic nerve activity in patients with EHT+DM2 and with DM2 relative to that in matched groups with EHT and normal blood pressure (NT). Methods and Results—In 68 closely matched subjects with EHT+DM2 (n=17), DM2 (n=17), EHT (n=17), and NT (n=17), we measured resting muscle sympathetic nerve activity as the mean frequency of multiunit bursts (MSNA) and of single units (s-MSNA) with defined vasoconstrictor properties. The s-MSNA in EHT+DM2 (97±3.8 impulses/100 beats) was greater (at least P <0.001) than in EHT (69±3.4 impulses/100 beats) and DM2 (78±4.1 impulses/100 beats), and all these were significantly greater (at least P <0.01) than in NT (53±3.3 impulses/100 beats) despite similar age and body mass index. The MSNA followed a similar trend. In addition, the level of insulin was also raised in EHT+DM2 (20.4±3.6 &mgr;U/mL) and DM2 (18.1±3.1 &mgr;U/mL; at least P <0.05) compared with HT or NT. Conclusions—Patients with EHT+DM2, EHT, or DM2 had central sympathetic hyperactivity, although plasma insulin levels were raised only in EHT+DM2 and DM2. The combination of EHT and DM2 resulted in the greatest sympathetic hyperactivity and level of plasma insulin, and this hyperactivity could constitute a mechanism for the increased risks of this condition.

Water ingestion increases sympathetic vasoconstrictor discharge in normal human subjects

A marked pressor response to water drinking has been observed in patients with autonomic failure and in the elderly, and has been attributed to sympathetic vasoconstrictor activation, despite the absence of such a pressor response in healthy subjects with intact sympathetic mechanisms. We investigated whether water drinking in normal subjects affected peripheral sympathetic neural discharge and its effect on vascular resistance. In nine normal human subjects, we examined the effect of water ingestion on muscle sympathetic neural activity from the peroneal nerve, as multi-unit bursts (muscle sympathetic nerve activity; MSNA) and as single-unit impulses (s-MSNA) with vasoconstrictor function, and on calf vascular resistance for 120 min. In each subject, water ingestion caused increases in s-MSNA and MSNA which peaked at 30 min after ingestion; they increased respectively (mean+/-S.E.M.) from 42+/-4 to 58+/-5 impulses/100 beats (P<0.01) and from 36+/-4 to 51+/-5 bursts/100 beats (P<0.001). There were corresponding increases in calf vascular resistance and in plasma noradrenaline levels. A significant correlation occurred between all of these data. In conclusion, measurement of MSNA has provided direct evidence that water drinking in normal human subjects increases sympathetic nerve traffic, leading to peripheral vasoconstriction. This sympathetic activation was not accompanied by significant changes in arterial blood pressure.

Disparity of autonomic control in type 2 diabetes mellitus

Aims/hypothesisAcute insulinaemia activates the sympathetic drive in a nonuniform manner. The extent and nature of such activation in type 2 diabetic patients who do not have neuropathy have not yet been addressed despite evidence relating sympathetic activation to cardiovascular risk. We planned to determine the magnitude and extent of the sympathetic drive and its reflex responses in patients with type 2 diabetes and fasting hyperinsulinaemia.MethodsWe measured resting muscle sympathetic nerve activity (MSNA) as the mean frequency of multi-unit bursts and single unit muscle sympathetic nerve activity (s-MSNA) in 17 overweight patients with type 2 diabetes and two matched normal control groups comprising 17 overweight and 16 normal-weight subjects. We also tested the MSNA and s-MSNA responses to cold pressor and isometric hand-grip tests, along with the effect of sympatho-vagal balance on heart period variability.ResultsBoth MSNA and s-MSNA in the group with type 2 diabetes (66±3.5 bursts/100 beats and 78±4.5 impulses/100 beats) were greater (at least p<0.0001) than in the overweight control group (42±2.6 bursts/100 beats and 48±3.4 impulses/100 beats) and normal-weight control group (43±6.2 bursts/100 beats and 51±7.1 impulses/100 beats), though the three groups had similar reflex responses, baroreflex sensitivity and sympatho-vagal balance controlling the heart period.Conclusions/interpretationThe patients with type 2 diabetes had no evidence of impaired reflex or autonomic control of heart period variability at a time when there was central sympathetic activation to the periphery. Furthermore, being overweight itself was not associated with sympathetic activation.

Sympathetic nerve hyperactivity is associated with increased peripheral vascular resistance in hypopituitary patients with growth hormone deficiency

objective Hypopituitary patients with untreated GH deficiency have increased cardiovascular mortality. Sustained vasoconstriction is an important factor in the development of hypertension and insulin resistance. This study was designed to see whether peripheral vascular resistance was increased in subjects with GH deficiency and to examine the mechanisms involved.

Sympathetic Activation and Vasoregulation in Response to Carbohydrate Ingestion in Patients With Congestive Heart Failure

BACKGROUND In normal individuals, carbohydrate ingestion increases sympathetic vasoconstrictor activity but causes net vasodilatation in the same vascular bed. This study quantified the effects of carbohydrate ingestion on muscle sympathetic nerve activity (MSNA) and vasoregulation in patients with congestive heart failure (CHF). We hypothesized that high resting levels of MSNA in patients with CHF would blunt further increases in MSNA following carbohydrate ingestion and that their sympathetic activation would restrain vasodilatation. METHODS Eleven patients with treated severe CHF and 11 age- and body mass index-matched normal controls (NCs) were studied for 2 hours after a high-carbohydrate meal. MSNA was measured by peroneal microneurography and calf blood flow by venous occlusion plethysmography. RESULTS Patients with CHF had higher (P < 0.03) baseline MSNA (67 ± 4.0 bursts/100 beats) than NCs (51 ± 5.8 bursts/100 beats) and lower (P < 0.001) baroreflex sensitivity (2.1 ± 0.58 ms/mm Hg) than NCs (7.4 ± 1.2 ms/mm Hg). Carbohydrate ingestion was associated with a significant increase in MSNA (P < 0.05) and calf blood flow (P < 0.01) with unchanged blood pressure in CHF patients. The magnitude of responses in CHF patients was not significantly different from that in NCs, but vasodilatation was delayed significantly (by 30 minutes). CONCLUSIONS Despite considerable resting sympathoexcitation and reduced baroreflex sensitivity, patients with CHF exhibited further increases in MSNA after carbohydrate ingestion, achieving levels similar to those after myocardial infarction. They also had temporally delayed vasodilatation, which could contribute to cachexia and muscle weakness in CHF patients. These observations suggest that high-carbohydrate meals may adversely affect CHF patients via altered autonomic tone and blood-flow patterns.

Intussusception as a gastrointestinal complication of diabetes: case report and literature review

This is the first reported case of intussusception in a patient with type 1 diabetes mellitus complicated by gastroparesis and autonomic neuropathy. Literature on the reported cases of intussusception in patients with diabetes, its aetiopathology and possible association with gastroparesis has been systematically reviewed following a Medline database search (1951 to June 2003) Intussusception should be considered in the differential diagnosis of gastrointestinal symptoms in diabetic patients presenting with hyperglycaemia. Br J Diabetes Vasc Dis 2004;4:408‐13

Could there be a role for metformin in type 1 and type 2 diabetic pregnancies

Keywords Metformin.Obesity.Pregnancy.Type 1 diabetes.Type 2 diabetesTo the Editor: We read with interest the systematic reviewby Vella et al. on the use of metformin in type 1 diabetes,which concludes that metformin therapy is associated withlower insulin requirements in that disease [1]. Given thecurrent epidemic of obesity, this is highly relevant becauseinsulin sparing in the treatment of type 1 diabetes may alsoattenuate weight gain, as shown in several small studies notincluded in the formal meta-analysis [2].Maternal obesity is rising. It is associated with a higherrisk of fetal and maternal complications, and is an indicatorof midlife obesity [3]. Pregnancy is associated withincreased insulin resistance, and high maternal insulinsecretion promotes maternal gestational weight gain andweight retention post-partum [4]. Ingestationaldiabetes,theuse of metformin has been associated with less weight gaininpregnancywithoutincreasedadverseoutcomes[5, 6]. Theeffect of metformin on weight gain in pregnant women withpre-existing diabetes is unknown.Metformin is not licensed for use in pregnancy.However, in view of growing supportive evidence, theNational Institute for Health and Clinical Excellence(NICE), the UK body responsible for national guidelineson clinical practice, approved its use in 2008. Our practicechanged then from solely using insulin to continuation ofmetformin in pregnant women with type 2 diabetes.We performed a case note review of 56 consecutivepregnancies with pre-existing diabetes (2006 to 2010) fromour clinic. The aim was to examine the extent of maternalweight gain and the effect of metformin use, with anemphasis on weight pre-pregnancy and at 6 months post-partum. Of the women included, 17 had type 2 diabetestreated with insulin alone during pregnancy, 17 had type 2diabetes and received metformin with or without insulin(three of whom received metformin alone throughoutpregnancy, with 14 requiring addition of insulin tometformin to meet their glycaemic targets) and 22 had type1 diabetes treated with insulin. There was no statisticaldifference in baseline characteristics (ethnicity, age, dura-tion of diabetes, parity, delivery week, HbA