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1.  New onset diabetes complicated by haemolysis and rhabdomyolysis: a case report and review of the literature 
Previously undiagnosed glucose-6-phosphate dehydrogenase (G6PD) deficiency can be unmasked by a diabetic crisis and both can be associated with rhabdomyolysis. The relationship between diabetes and G6PD deficiency is discussed and the possible triggers for haemolysis as outlined in this case report. The incidence of G6PD deficiency is 10% in African-American males and up to 35% in parts of Africa so an increased awareness of G6PD deficiency is important when treating diabetes in these populations.
Case presentation
A 54-year-old Kenyan man presented with a 3-day history of reduced appetite, weakness and reduced level of consciousness as a result of a hyperglycaemic diabetic crisis with both hyperosmolarity and ketoacidosis. The patient then developed haemolysis and a raised creatine kinase level. A diagnosis of G6PD deficiency and rhabdomyolysis was made.
This case highlights the importance of simple laboratory investigations in the early identification of the rarer complications of diabetic crisis such as haemolysis secondary to G6PD deficiency and rhabdomyolysis.
PMCID: PMC2440389  PMID: 18485212
2.  Effect of acute hyperglycaemia and/or hyperinsulinaemia on proinflammatory gene expression, cytokine production and neutrophil function in humans 
Diabetic Medicine  2008;25(2):157-164.
Type 2 diabetes is frequently associated with infectious complications. Swift activation of leucocytes is important for an adequate immune response. We determined the selective effects of hyperglycaemia and hyperinsulinaemia on lipopolysaccharide (LPS)-induced proinflammatory gene expression and cytokine production in leucocytes and on neutrophil functions.
Six healthy humans were studied on four occasions for 6 h during: (i) lower insulinaemic euglycaemic clamp, (ii) lower insulinaemic hyperglycaemic clamp, (iii) hyperinsulinaemic euglycaemic clamp, and (iv) hyperinsulinaemic hyperglycaemic clamp. Target levels of plasma glucose were 12.0 mmol/l (hyperglycaemic clamps) or 5.0 mmol/l (euglycaemic clamps). Target plasma insulin levels were 400 pmol/l (hyperinsulinaemic clamps) or 100 pmol/l (lower insulinaemic clamps).
Hyperglycaemia reduced LPS-induced mRNA expression of nuclear factor of κ light polypeptide gene enhancer in B cells inhibitor alpha (NFKBIA), interleukin-1 alpha (IL1A) and chemokine (C-C motif) ligand 3 (CCL3), whereas during hyperinsulinaemia enhanced mRNA levels occurred in six out of eight measured inflammation-related genes, irrespective of plasma glucose levels. Combined hyperglycaemia and hyperinsulinaemia led to enhanced IL1A, interleukin-1 beta (IL1B) and CCL3 mRNA levels upon LPS stimulation. Neither hyperglycaemia nor hyperinsulinaemia altered cytokine protein production, neutrophil migration, phagocytic capacity or oxidative burst activity.
These results suggest that short-term hyperglycaemia and hyperinsulinaemia influence the expression of several inflammatory genes in an opposite direction, that the acute effects of hyperinsulinaemia on inflammatory mRNA levels may be stronger than those of hyperglycaemia, and that the effects of insulin, in particular, may be relevant in the concurrent presence of hyperglycaemia.
Diabet. Med. 25, 157–164 (2008)
PMCID: PMC2268957  PMID: 18290856
cytokines; hyperglycaemia; hyperinsulinaemia; mRNA; neutrophils
3.  Clinical features, predictive factors and outcome of hyperglycaemic emergencies in a developing country 
Hyperglycaemic emergencies are common acute complications of diabetes mellitus (DM) but unfortunately, there is a dearth of published data on this entity from Nigeria. This study attempts to describe the clinical and laboratory scenario associated with this complication of DM.
This study was carried out in DM patients who presented to an urban hospital in Nigeria with hyperglycaemic emergencies (HEs). The information extracted included biodata, laboratory data and hospitalization outcome. Outcome measures included mortality rates, case fatality rates and predictive factors for HEs mortality. Statistical tests used are χ2, Student's t test and logistic regression.
A total of 111 subjects with HEs were recruited for the study. Diabetes ketoacidosis (DKA) and hyperosomolar hyperglycaemic state (HHS) accounted for 94 (85%) and 17 (15%) respectively of the HEs. The mean age (SD) of the subjects was 53.9 (14.4) years and their ages ranged from 22 to 86 years. DKA occurred in all subjects with type 1 DM and 73 (81%) of subjects with type 2 DM. The presence of HSS was noted in 17 (19%) of the subjects with type 2 DM.
Hypokalaemia (HK) was documented in 41 (37%) of the study subjects. Elevated urea levels and hyponatraemia were noted more in subjects with DKA than in those subjects with HHS (57.5%,19% vs 53%,18%). The mortality rate for HEs in this report is 20% and the case fatality rates for DKA and HHS are 18% and 35% respectively.
The predictive factors for HEs mortality include, sepsis, foot ulceration, previously undetected DM, hypokalaemia and being elderly.
HHS carry a higher case fatality rate than DKA and the predictive factors for hyperglycaemic emergencies' mortality in the Nigerian with DM include foot ulcers, hypokalaemia and being elderly.
PMCID: PMC2661082  PMID: 19272167
4.  An investigation of factors associated with psychiatric hospital admission despite the presence of crisis resolution teams 
BMC Psychiatry  2007;7:52.
Crisis resolution teams (CRTs) provide a community alternative to psychiatric hospital admission for patients presenting in crisis. Little is known about the characteristics of patients admitted despite the availability of such teams.
Data were drawn from three investigations of the outcomes of CRTs in inner London. A literature review was used to identify candidate explanatory variables that may be associated with admission despite the availability of intensive home treatment. The main outcome variable was admission to hospital within 8 weeks of the initial crisis. Associations between this outcome and the candidate explanatory variables were tested using first univariate and then multivariate analysis.
Patients who were uncooperative with initial assessment (OR 10.25 95% CI-4.20–24.97), at risk of self-neglect (OR 2.93 1.42–6.05), had a history of compulsory admission (OR 2.64 1.07–6.55), assessed outside usual office hours (OR 2.34 1.11–4.94) and/or were assessed in hospital casualty departments (OR 3.12 1.55–6.26), were more likely to be admitted. Other than age, no socio-demographic features or diagnostic variables were significantly associated with risk of admission.
With the introduction of CRTs, inpatient wards face a significant challenge, as patients who cooperate little with treatment, neglect themselves, or have previously been compulsorily detained are especially likely to be admitted. The increased risk of admission associated with casualty department assessment may be remediable.
PMCID: PMC2148041  PMID: 17910756
5.  Hyperglycaemic index as a tool to assess glucose control: a retrospective study 
Critical Care  2004;8(3):R122-R127.
Critically ill patients may benefit from strict glucose control. An objective measure of hyperglycaemia for assessing glucose control in acutely ill patients should reflect the magnitude and duration of hyperglycaemia, should be independent of the number of measurements, and should not be falsely lowered by hypoglycaemic values. The time average of glucose values above the normal range meets these requirements.
A retrospective, single-centre study was performed at a 12-bed surgical intensive care unit. From 1990 through 2001 all patients over 15 years, staying at least 4 days, were included. Admission type, sex, age, Acute Physiology and Chronic Health Evaluation II score and outcome were recorded. The hyperglycaemic index (HGI) was defined as the area under the curve above the upper limit of normal (glucose level 6.0 mmol/l) divided by the total length of stay. HGI, admission glucose, mean morning glucose, mean glucose and maximal glucose were calculated for each patient. The relations between these measures and 30-day mortality were determined.
In 1779 patients with a median stay in the intensive care unit of 10 days, the 30-day mortality was 17%. A total of 65,528 glucose values were analyzed. Median HGI was 0.9 mmol/l (interquartile range 0.3–2.1 mmol/l) in survivors versus 1.8 mmol/l (interquartile range 0.7–3.4 mmol/l) in nonsurvivors (P < 0.001). The area under the receiver operator characteristic curve was 0.64 for HGI, as compared with 0.61 and 0.62 for mean morning glucose and mean glucose. HGI was the only significant glucose measure in binary logistic regression.
HGI exhibited a better relation with outcome than other glucose indices. HGI is a useful measure of glucose control in critically ill patients.
PMCID: PMC468891  PMID: 15153239
critically ill patients; hyperglycaemia; normoglycaemia; outcome prognosis
6.  The prevalence and ingredient cost of chronic comorbidity in the Irish elderly population with medication treated type 2 diabetes: A retrospective cross-sectional study using a national pharmacy claims database 
Comorbidity in patients with diabetes is associated with poorer health and increased cost. The aim of this study was to investigate the prevalence and ingredient cost of comorbidity in patients ≥ 65 years with and without medication treated type 2 diabetes using a national pharmacy claims database.
The Irish Health Service Executive Primary Care Reimbursement Service pharmacy claims database, which includes all prescribing to individuals covered by the General Medical Services scheme, was used to identify the study population (≥ 65 years). Patients with medication treated type 2 diabetes (T2DM) were identified using the prescription of oral anti-hyperglycaemic agents alone or in combination with insulin as a proxy for disease diagnosis. The prevalence and ingredient prescribing cost of treated chronic comorbidity in the study population with and without medication treated T2DM were ascertained using a modified version of the RxRiskV index, a prescription based comorbidity index. The association between T2DM and comorbid conditions was assessed using logistic regression adjusting for age and sex. Bootstrapping was used to ascertain the mean annual ingredient cost of treated comorbidity. Statistical significance at p < 0.05 was assumed.
In 2010, 43165 of 445180 GMS eligible individuals (9.7%) were identified as having received medication for T2DM. The median number of comorbid conditions was significantly higher in those with T2DM compared to without (median 5 vs. 3 respectively; p < 0.001). Individuals with T2DM were more likely to have ≥ 5 comorbidities when compared to those without (OR = 2.82, 95% CI = 2.76-2.88, p < 0.0001). The mean annual ingredient cost for comorbidity was higher in the study population with T2DM (€1238.67, 95% CI = €1238.20 - €1239.14) compared to those without the condition (€799.28, 95% CI = €799.14 - € 799.41).
Individuals with T2DM were more likely to have a higher number of treated comorbid conditions than those without and this was associated with higher ingredient costs. This has important policy and economic consequences for the planning and provision of future health services in Ireland, given the expected increase in T2DM and other chronic conditions.
PMCID: PMC3554499  PMID: 23324517
Comorbidity; Type 2 diabetes; Pharmacoepidemiology; RxRisk V index; Ireland; Ingredient cost; Elderly
7.  Diabetic and endocrine emergencies 
Postgraduate Medical Journal  2007;83(976):79-86.
Endocrine emergencies constitute only a small percentage of the emergency workload of general doctors, comprising about 1.5% of all hospital admission in England in 2004–5. Most of these are diabetes related with the remaining conditions totalling a few hundred cases at most. Hence any individual doctor might not have sufficient exposure to be confident in their management. This review discusses the management of diabetic ketoacidosis, hyperosmolar hyperglycaemic state, hypoglycaemia, hypercalcaemia, thyroid storm, myxoedema coma, acute adrenal insufficiency, phaeochromocytoma hypertensive crisis and pituitary apoplexy in the adult population.
PMCID: PMC2805944  PMID: 17308209
8.  The role of pancreatic insulin secretion in neonatal glucoregulation. II. Infants with disordered blood glucose homoeostasis. 
Archives of Disease in Childhood  1993;68(3 Spec No):280-285.
Some neonates, such as those who are preterm or small for dates, become hypoglycaemic or hyperglycaemic. These disorders represent a failure of neonatal metabolic adaptation, but the underlying mechanisms are unclear. Data from studies of hypoglycaemic and hyperglycaemic infants were reviewed in the light of new data from studies of healthy neonates. Data from 28 neonates, who had disordered blood glucose homoeostasis, were analysed to determine the interrelationships between circulating concentrations of glucose, intermediary metabolites, glucagon and insulin, and glucose production rates. Blood glucose concentrations ranged from 2.5 to 26.1 mmol/l, and glucose production rates from 0 to 19.2 mg/kg/min. Blood glucose concentrations were positively related to intravenous glucose infusion rates and to glucose production rates. A negative relationship existed between plasma glucagon and blood glucose concentrations, but there was a wide variation in plasma insulin levels at all blood glucose concentrations. No relationship between either plasma insulin or glucagon concentration and glucose production rate was shown. It is concluded that in neonates with disordered blood glucose homoeostasis, blood glucose concentration is influenced by the rate of administration of glucose, with less precise internal control mechanisms than older subjects. This emphasises the importance of blood glucose monitoring and careful prescribing of exogenous glucose by clinicians caring for such infants.
PMCID: PMC1590378  PMID: 8466263
9.  Small bowel infarction associated with pancreatic glucagonoma. 
Postgraduate Medical Journal  1990;66(780):874-875.
An 88 year old woman presented comatose, hypothermic and hyperglycaemic. She died soon after admission and at autopsy recent small bowel infarction was found. The superior mesenteric artery was encased in a dense pancreatic mass and there was marked luminal narrowing of the vessel. Histology revealed a pancreatic glucagonoma which had metastasized to colonic submucosa and serosa. Glucagonoma is a rare tumour and this presentation of small bowel infarction associated with pancreatic glucagonoma would appear to be a unique event.
PMCID: PMC2429709  PMID: 2099438
10.  Antidiabetic and Cytotoxicity Screening of Five Medicinal Plants Used by Traditional African Health Practitioners in the Nelson Mandela Metropole, South Africa 
Diabetes mellitus is a growing problem in South Africa and of concern to traditional African health practitioners in the Nelson Mandela Metropole, because they experience a high incidence of diabetic cases in their practices. A collaborative research project with these practitioners focused on the screening of Bulbine frutescens, Ornithogalum longibracteatum, Ruta graveolens, Tarchonanthus camphoratus and Tulbaghia violacea for antidiabetic and cytotoxic potential. In vitro glucose utilisation assays with Chang liver cells and C2C12 muscle cells, and growth inhibition assays with Chang liver cells were conducted. The aqueous extracts of Bulbine frutescens (143.5%), Ornithogalum longibracteatum (131.9%) and Tarchonanthus camphoratus (131.5%) showed significant increased glucose utilisation activity in Chang liver cells. The ethanol extracts of Ruta graveolens (136.9%) and Tulbaghia violacea (140.5%) produced the highest increase in glucose utilisation in C2C12 muscle cells. The ethanol extract of Bulbine frutescens produced the most pronounced growth inhibition (33.3%) on Chang liver cells. These findings highlight the potential for the use of traditional remedies in the future for the management of diabetes and it is recommended that combinations of these plants be tested in future.
PMCID: PMC3252689  PMID: 22238496
Diabetes mellitus; Cytotoxicity; Collaborative research; Chang liver cells; C2C12 muscle cells
11.  Mannose-binding lectin plays a critical role in myocardial ischaemia and reperfusion injury in a mouse model of diabetes 
Diabetologia  2008;51(8):1544-1551.
Diabetic patients are at increased risk of cardiomyopathy, acute myocardial infarction and loss of cardiac progenitor cells (CPCs), but the aetiology is poorly understood. We hypothesised a significant role for mannose-binding lectin (MBL) in cardiomyopathies associated with hyperglycaemia.
The role of MBL in myocardial ischaemia and reperfusion (MI/R) injury was investigated in wild-type (WT) and MBL-null mice following 2 weeks of streptozotocin-induced hyperglycaemia.
Hyperglycaemic WT mice presented with significantly decreased left ventricular ejection fractions and increased serum troponin I levels and myocardial inflammation compared with non-diabetic WT mice following MI/R. Hyperglycaemic MBL-null mice or insulin-treated diabetic WT mice were significantly protected from MI/R injury compared with diabetic WT mice. In an additional study using diabetic WT mice, echocardiographic measurements demonstrated signs of dilative cardiomyopathy, whereas heart:body weight ratios suggested hypertrophic cardiac remodelling after 2 weeks of hyperglycaemia. Immunohistochemical analysis of CPCs showed significantly lower numbers in diabetic WT hearts compared with non-diabetic hearts. Insulin-treated diabetic WT or untreated diabetic MBL-null mice were protected from dilative cardiomyopathy, hypertrophic remodelling and loss of CPCs.
These data demonstrate that MBL may play a critical role in diabetic MI/R injury. Further, the absence of MBL appears to inhibit hypertrophic remodelling and hyperglycaemia-induced loss of CPCs after just 2 weeks of hyperglycaemia in mice.
PMCID: PMC2542900  PMID: 18493734
Animal; Complement; Mannose-binding lectin; Type 1 diabetes
12.  Myocardial ischaemia in sickle cell anaemia: evaluation using a new scoring system 
Annals of tropical paediatrics  2011;31(1):67-74.
Sickle cell anaemia (SCA) is associated with recurrent multi-organ ischaemia and infarction. Myocardial ischaemia (MI) and infarction are increasingly recognised as features of SCA. The prevalence and severity of MI in children with SCA is not known.
To evaluate the usefulness of a new scoring system based on the standard surface electrocardiogram (ECG) in determining the prevalence and severity of MI in children with SCA.
MI prevalence and scores derived from standard surface ECGs of 35 children with SCA aged 3–18 years who presented consecutively during 38 episodes of vaso-occlusive crisis (VOC) were compared with those of 40 age- and sex-matched SCA patients in the steady state and 40 anaemic non-SCA patients. In SCA subjects with VOC, ECG was repeated approximately 1 week and 4–8 weeks post crisis and the respective MI scores were compared with their intra-crisis ECG and those of the two other groups.
Mean (SD) MI scores were significantly higher during vaso-occlusive crises [1.82 (0.20)] compared with the steady state [1.15 (0.15)] and non-SCA anaemic controls [1.13 (0.21)], p=0.017. SCA patients in crisis were 5.5 (1.20–13.99) times more likely to have MI compared with non-SCA anaemic controls (p=0.025). They were also 3.66 (1.05–12.74, p=0.042) and 7.58 (1.31–43.92, p=0.024) times more likely to have mild and significant MI, respectively. MI scores derived from the post-crisis ECGs were similar to those of steady-state SCA patients.
ECG changes consistent with MI are common in children with SCA, especially during vaso-occlusive crises. Our proposed MI scoring system could be a useful screening tool for early detection of significant MI during crises, facilitating early institution of intervention. Further studies are needed to determine the specificity of the observed changes and to validate the proposed screening tool.
PMCID: PMC3040492  PMID: 21262112
13.  Effects of hyperglycaemia and sorbitol accumulation on erythrocyte deformability in diabetes mellitus. 
Journal of Clinical Pathology  1986;39(7):722-727.
Erythrocyte deformability was studied in a total of 83 poorly controlled diabetics (mean blood glucose 12.2 mmol/l) who were divided into three groups, each with matched healthy controls. There was no appreciable difference between diabetics and matched controls regarding the filtration of erythrocytes through 3 micron diameter straight channel pores (25 diabetics) or tortuous channel pores (28 diabetics), or for the measurement of erythrocyte elongation over a range of osmolalities in the Ektacytometer (30 diabetics). When erythrocytes from 17 additional diabetics and 17 healthy controls were incubated for two hours at 37 degrees C in hyperglycaemic (50 mmol glucose/l) buffer, however, there was a considerable reduction in erythrocyte filterability for both diabetics and controls in parallel with an increase in erythrocyte sorbitol concentration. This loss of filterability was prevented by the addition of an aldose reductase inhibitor (Sorbinil). High glucose concentrations (congruent to 50 mmol/l) impair the filterability of erythrocytes through 3 micron pores, and the intracellular accumulation of sorbitol in poorly controlled outpatients is therefore unlikely to have a major adverse effect on erythrocyte rheology in diabetes mellitus.
PMCID: PMC500031  PMID: 3090107
14.  Short-term mortality of myocardial infarction patients with diabetes or hyperglycaemia during admission 
Aim: The hypothesis that patients with hyperglycaemia during admission, regardless of previous diagnosis of diabetes, have worse prognosis than those with normal glucose values is controversial. The objective was to assess the role of hyperglycaemia on short-term mortality after myocardial infarction (MI).
Methods and Results: A cohort study nested in a prospective registry of MI patients in the reference hospital of Gerona, Spain was performed. All consecutive MI patients under 75 were registered between 1993 and 1996. Patient and clinical characteristics, including previous diagnosis of diabetes, glycaemia on admission and in the next four days, were recorded. Patients with glycaemia on admission or four day mean glycaemia >6.67 mmol/l were considered hyperglycaemic. The main outcome measure was mortality at 28 days. Of 662 patients with MI included, 195 (29.7%) had previously known diabetes mellitus, but 457 (69.0%) had glycaemia >6.67 mmol/l on admission. Patients with hyperglycaemia on admission were older, more often female, more frequently had a previous diagnosis of diabetes, developed more complications, and had higher 28 day mortality. The effect of admission glycaemia >6.67 mmol/l on 28 day mortality was independent of major confounding factors, particularly previous diagnosis of diabetes (OR=4.20, 95% confidence intervals 1.18 to 14.96).
Conclusions: Higher 28 day mortality was observed among MI patients with glycaemia on admission >6.67 mmol/l compared with patients with lower levels, independently of major confounding variables and, particularly, previous diagnosis of diabetes. This early, simple, and inexpensive marker of bad prognosis after MI should prompt the application of more aggressive treatment of MI and risk factors and, probably, of glycaemia during admission.
PMCID: PMC1732251  PMID: 12177090
15.  A new immunodeficient hyperglycaemic mouse model based on the Ins2Akita mutation for analyses of human islet and beta stem and progenitor cell function 
Diabetologia  2008;51(8):1449-1456.
To develop and validate a new immuno-deficient mouse strain that spontaneously develops a non-autoimmune hyperglycaemia to serve as a diabetic host for human islets and human beta stem and progenitor cells without the need for induction of hyperglycaemia by toxic chemicals with their associated side effects.
We generated and characterised a new strain of immunodeficient spontaneously hyperglycaemic mice, the NOD-Rag1null Prf1null Ins2Akita strain and compared this strain with the NOD-scidIl2rγnull (also known as Il2rg) immunodeficient strain rendered hyperglycaemic by administration of a single dose of streptozotocin. Hyperglycaemic mice were transplanted with human islets ranging from 1,000 to 4,000 islet equivalents (IEQ) and were monitored for normalisation of blood glucose levels.
NOD-Rag1null Prf1null Ins2Akita mice developed spontaneous hyperglycaemia, similar to Ins2Akita-harbouring strains of immunocompetent mice. Histological examination of islets in the host pancreas validated the spontaneous loss of beta cell mass in the absence of mononuclear cell infiltration. Human islets transplanted into spontaneously diabetic NOD-Rag1null Prf1null Ins2Akita and chemically diabetic NOD-scid Il2rγnull mice resulted in a return to euglycaemia that occurred with transplantation of similar beta cell masses.
The NOD-Rag1null Prf1null Ins2Akita mouse is the first immunodeficient, spontaneously hyperglycaemic mouse strain described that is based on the Ins2Akita mutation. This strain is suitable as hosts for human islet and human beta stem and progenitor cell transplantation in the absence of the need for pharmacological induction of diabetes. This strain of mice also has low levels of innate immunity and can be engrafted with a human immune system for the study of human islet allograft rejection.
PMCID: PMC2719841  PMID: 18563383
Akita; Humanised mice; Insulin; Islet transplantation; NOD mice
16.  Non-ketotic hyperglycaemic chorea: a SPECT study. 
OBJECTIVE: To study regional blood flow of the striatum in non-ketotic hyperglycaemic choreic patients. METHODS: Brain SPECT was performed with intravenous injection of 20 mCi 99mTc hexamethylpropylene amineoxime in six non-ketotic hyperglycaemic choreic patients and 10 age matched patients with a similar level of hyperglycaemia without chorea as a control. The focal perfusion defects were analysed by visual interpretation and semiquantitative determination with reference to homolateral occipital blood flow. RESULTS: The measured blood flow of striatum on the contralateral side of chorea was significantly decreased. CONCLUSIONS: Hypometabolism of the striatum is seen not only in Huntington's disease, but also in non-ketotic hyperglycaemic chorea. Hypofunction of the striatum is a possible common pathogenesis in the development of contralateral chorea in different diseases. Furthermore, the sensitivity and reliability of SPECT is as good as PET in assessing choreic patients.
PMCID: PMC1073898  PMID: 8774410
17.  The Novel Antihyperglycaemic Action of Hunteria Umbellata Seed Fractions Mediated Via Intestinal Glucose Uptake Inhibition 
The present study evaluated the antihyperglycaemic effect and mechanism of action of fractions of the aqueous seed extract of Hunteria umbellata (K. Schum.) Hallier f. (HU) in normal and alloxan-induced hyperglycaemic rats. HU was partitioned in chloroform, acetyl acetate and butan-1-ol to give chloroform fraction (HUc), ethyl acetate fraction (HUe), butanol fraction (HUb) and the “residue” (HUm), respectively. 200 mg/kg of each of these fraction dissolved in 5% Tween 20 in distilled water was investigated for its acute oral hypoglycaemic effects in normal rats over 6 hours while its repeated dose antihyperglycaemic effect was evaluated in alloxan-induced hyperglycaemic rats over 5 days. In addition, 50 mg/kg of the crude alkaloid fraction (HUAf) extracted from HU was evaluated for its possible antihyperglycaemic activity in alloxaninduced hyperglycaemic rats using oral glucose tolerance test (OGTT) over 6 hours. Using the solvent system, distilled water-butanol-ammonium hydroxide (2:15:1, v/v/v), HUb was chromatographed and stained with Dragendorff's reagent for confirmatory qualitative analysis for alkaloids. Results showed that oral pre-treatment with 200 mg/kg of HUe, HUb and HUm resulted in a significant (p<0.05, p<0.001) time dependent hypoglycaemic effect, with the butan-1-ol fraction HU causing the most significant (p<0.001) hypoglycaemic effect. In the alloxan-induced hyperglycaemic rats, repeated oral treatment with 200 mg/kg of same HU fractions for 5 days resulted in significant (p<0.05) decreases in the fasting blood glucose concentrations with the most significant (p<0.01) antihyperglycaemic effect also recorded for HUb. Similarly, oral pretreatment with 50 mg/kg of HUAf significantly (p<0.05, p<0.01 and p<0.001) attenuated an increase in the post-absorptive glucose concentration at 1st – 6th h in the alloxan-induced hyperglycaemic OGTT model. In addition, alkaloid was present in most of the separated spots on the TLC plate. In conclusion, results of this study showed that HU contains a relative high amount of alkaloids which could have accounted for the antihyperglycaemic action of HU that was mediated via intestinal glucose uptake inhibition.
PMCID: PMC3744210  PMID: 23983315
Hunteria umbellata aqueous seed extract; Alkaloid fraction; Intestinal glucose uptake inhibition; Normal and alloxan-induced hyperglycaemic rats
18.  Blood pressure response to glucose potassium insulin therapy in patients with acute stroke with mild to moderate hyperglycaemia 
Insulin is neuroprotective in animal stroke models but its effects in acute stroke in humans are unknown. The Glucose Insulin in Stroke Trial (GIST-UK) is a randomised controlled trial investigating the benefits of maintaining euglycaemia in hyperglycaemic patients with acute stroke. Data are reported from a GIST-UK substudy which sought to determine the influence of glucose potassium insulin (GKI) infusion on blood pressure in acute stroke. All adult patients admitted to hospital with acute stroke with hyperglycaemia (plasma glucose 6.1-17 mmol/l) were potentially eligible. Randomised patients received either a GKI infusion (500 ml 10% glucose, 20 mmol potassium chloride, 16 units of insulin) or control therapy with 154 mmol/l (0.9%) saline at 100 ml/h for 24 hours. BM test strip glucose monitoring was performed 2 hourly, blood pressure monitoring 4hourly, and plasma glucose sampling 8 hourly. Insulin concentration in the GKI infusate was altered according to test strip values to maintain test strip values between 4-7 mmol/l in the GKI group. Neurological impairment was determined using the European stroke scale (ESS). 145 patients were studied (73 GKI, 72 control). Mean systolic blood pressure was significantly lower during GKI infusion between 4 hours and 24 hours except at 8 hours. Median total ESS scores improved significantly between admission and day 7 in the GKI group (p<0.001) although there was no significant difference in total ESS score between groups at day 7. The significant reduction of systolic blood pressure in acute stroke associated with GKI therapy was not associated with neurological deterioration and may have been beneficial.

PMCID: PMC1737285  PMID: 11181869
19.  Increased chromosomal stability in cultures of ovarian tumours of low malignant potential compared to cystadenomas 
British Journal of Cancer  2007;96(12):1908-1913.
Cell cultures of ovarian cystadenomas transfected with SV40 large T antigen are not immortal because they invariably reach a phenomenon called crisis, which is triggered in part by telomere attrition. Recovery from crisis may be an integral component of the malignant transformation process. We reported earlier that such ovarian cystadenoma cell cultures undergo severe changes in DNA ploidy as they approach crisis and that such changes are an important determinant of crisis independent of telomere attrition. Here, we show that in sharp contrast to these benign ovarian tumours, the DNA content of ovarian tumours of low malignant potential (LMP) was remarkably stable as they approached crisis, suggesting that telomere attrition was the main determinant of this mortality checkpoint. Lack of a ploidy-based crisis was not due to loss of expression of a functional SV40 large T antigen protein. We conclude that ovarian LMP tumours are characterised by increased numerical chromosomal stability compared to cystadenomas. This might account for the fact that most LMP tumours are diploid or near diploid in vivo. This fundamental difference in chromosomal stability between ovarian cystadenomas and LMP tumours also suggests potential differences in predisposition to progression to malignancy between these two ovarian tumour subtypes.
PMCID: PMC2359981  PMID: 17519898
ovarian neoplasms; cellular aging; telomeres; aneuploidy; chromosomal stability
20.  Redefinition of gestational diabetes mellitus: implications for laboratory practice in Croatia 
Biochemia Medica  2013;23(1):7-11.
An increasing prevalence of gestational diabetes has become a very challenging task in prenatal care worldwide. International Association of Diabetes and Pregnancy Study Groups (IADPSG) has recently issued recommendations on the diagnosis and classification of hyperglycaemia in pregnancy. These recommendations, the first to provide harmonised, evidence-based criteria for the diagnosis and classification of diabetes in pregnancy, are currently being discussed and accepted worldwide by the relevant authorities. As the acceptance of the proposed criteria has major implications for both clinical and laboratory settings, a concerted action towards necessary changes in practice has to be carefully planned and adjusted to national health-care specificities.
IADPSG criteria have been strongly advocated by the Croatian Perinatology Society, resulting in a new strategy for the detection and diagnosis of hyperglycaemic disorders in pregnancy.
To address the respective laboratory requirements, in April 2012, the Croatian Chamber of Medical Biochemists appointed a Working Group to provide a standardised procedure for the diagnosis of gestational diabetes, applicable to all laboratories involved in prenatal care, in both primary and specialised health-care facilities.
In this paper we discuss key laboratory-related issues regarding succesful implementation of the IADPSG criteria in Croatia.
PMCID: PMC3900087  PMID: 23457760
gestational diabetes; IADPSG criteria; clinical laboratory techniques
21.  Stroke topography and outcome in relation to hyperglycaemia and diabetes. 
In a prospective study to analyse stroke topography and outcome in diabetics and to determine the prognostic value of blood glucose and glycosylated haemoglobin estimation, we evaluated 176 patients with acute stroke. The patients were classified into four groups on the basis of history, fasting glucose, and glycosylated haemoglobin: euglycaemic patients with no history of diabetes, stress hyperglycaemia, newly diagnosed diabetics, and known diabetics. A high prevalence of undiagnosed diabetes was shown. No difference was found in the type or site of stroke between the four groups. No difference was found in the site of symptomatic or incidental lesions on computerised axial tomography. Patients with stress hyperglycaemia and known diabetics had more severe strokes. Mortality was higher in patients with stress hyperglycaemia, newly diagnosed diabetics, and the combined diabetes groups. This increased mortality was evident in the hyperglycaemic and diabetic groups, even after excluding patients with cerebral haemorrhage. Stroke severity and mortality also increased independently with blood glucose in the euglycaemic group. We conclude that there is a correlation between admission glucose concentration, diabetes, and poor stroke outcome, which may not be attributed to stroke type or location.
PMCID: PMC489037  PMID: 1583510
22.  On the Management of Hyperglycaemia in Critically Ill Patients Undergoing Surgery 
Hyperglycaemia is a major health risk and a negative determinant of surgical outcome. Despite its increasing prevalence, the limited treatments for restoration of normoglycaemia make its effective management a highly complex individualized clinical art. In this context, we review the mechanisms leading to hyperglycaemic damage as the basis for effective management of surgical complications of diabetic and non diabetic critically ill patients.
PMCID: PMC3409618  PMID: 22870170
Hyperglycaemia; Surgical complications; Critically ill patients
23.  The perils of high carbohydrate drinks in the undiagnosed diabetic patient 
BMJ Case Reports  2011;2011:bcr0720103191.
Diabetes mellitus is increasing in its incidence and prevalence. Reduction in refined carbohydrate (sugar) intake is an important part of nutritional advice to patients with known diabetes. Sugar is available in a variety of confectionary products. It is also available in especially packaged ‘convenience foods’ as high energy drinks. Among people without diabetes, such food can have its own health risks.
A significant group of patients with diabetes remain undiagnosed. This group are at especially high risk from all the negative metabolic effects of high sugar intake available as high calorie drinks.
The authors report two patients without previously known diabetes who presented similarly with marked hyperglycaemic states, leading to severe metabolic disturbances. Both were obese, had common precipitating factors and consumed large quantities of sugary soft drinks (‘lucozade’). Both patients recovered well. They were followed up for over 7 years. One is not diabetic and the second is diabetic requiring a small dose of metformin.
PMCID: PMC3158358  PMID: 22688486
24.  PA01.58. Role of laghu malini vasanta rasa in management of madhumeha, type 2 diabetes mellitus 
Ancient Science of Life  2012;32(Suppl 1):S108.
Laghu Malini Vasanta Rasa is a Vasanta Malati Kalpa with Rasaka and Maricha as main ingredients, chiefly acting on Dhatvagni with Brimhana effect. It had been quoted by 30 texts and mentioned under Jeerna Jwaradhikara. None of text had mentioned it for Madhumeha. Madhumeha is chronic disorder where Dhatvagnimandya leads to diminution of Prasada Dhatu resulting in Vataprakopa. Type 2 Diabetes Mellitus is more prevalent among other types 62.4 million in 2011. Long termed hyperglycemia in Type 2 DM results in decreased quality of life 2.263 million disability adjusted life years in India during 2004. Through present study attempt was made to evaluate efficacy of formulation (AFI part I 20:36) in Madhumeha as anti-hyperglycaemic activity of ingredients of Laghu Malini Vasanta Rasa has been recognized.
Open trial (CTRI registration no. CTRI/2011/11/00211) Inclusion criteria-Age group 30 60 yrs, Patients with cardinal symptoms of Madhumeha Exclusion criteria-Age group <30 >60yrs, Accelerated HTN, Pregnant, Lactating mother, CNS complication Diagnostic criteria-Subjective criteria: Classical signs & symptoms of Madhumeha, Objective criteria: FBS (fasting blood sugar) >126 mg/dl OR PPBSL (postprandial blood sugar level) >200 mg/dl, Total Reg.patient-33; completed-30; Dropped out-3, Posology with duration of treatment: 250mg tablet BD 30 min. before meal with lukewarm water for 8 weeks. Criteria for assessment: Relief in symptoms by Wilcoxson signed rank method. Unpaired t test for statistical analysis of objective parameters.
Highly significant relief p < 0.001in symptoms Klama, Daurbalya and significant relief P < 0.05 in reducing urine sugar and PPBSL (postprandial blood sugar level).
Laghu Malini Vasanta helped to improve quality of life in-patient of Madhumeha.
PMCID: PMC3800861
25.  Mutations in Mll2, an H3K4 Methyltransferase, Result in Insulin Resistance and Impaired Glucose Tolerance in Mice 
PLoS ONE  2013;8(6):e61870.
We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7) gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes) died during embryonic development at 9.5–14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level.
PMCID: PMC3691224  PMID: 23826075

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