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1.  Endocrine-related diseases in the emergency unit of a Tertiary Health Care Center in Lagos: A study of the admission and mortality patterns 
Introduction:
Non-communicable diseases are emerging as an important component of the burden of diseases in developing countries. Knowledge on admission and mortality patterns of endocrine-related diseases will give insight into the magnitude of these conditions and provide effective tools for planning, delivery, and evaluation of health-care needs relating to endocrinology.
Materials and Methods:
We retrieved medical records of patients that visited the emergency unit of the Lagos University Teaching hospital, over a period of 1 year (March 2011 to February 2012) from the hospital admissions and death registers. Information obtained included: Age, gender, diagnosis at admission and death, co-morbidities. Diagnoses were classified as endocrine-related and non-endocrine related diseases. Records with incomplete data were excluded from the study.
Results:
A total of 1703 adult medical cases were seen; of these, 174 were endocrine-related, accounting for 10.2% of the total emergency room admission in the hospital. The most common cause of endocrine-related admission was hyperglycaemic crises, 75 (43.1%) of cases; followed by diabetes mellitus foot syndrome, 33 (19.0%); hypoglycaemia 23 (13.2%) and diabetes mellitus related co-morbidities 33 (19.0%). There were 39 endocrine-related deaths recorded. The result revealed that 46.1% of the total mortality was related to hyperglycaemic emergencies. Most of the mortalities were sepsis-related (35.8%), with hyperglycaemic crises worst affected (71.42%). However, the case fatalities were highest in subjects with thyrotoxic crisis and hypoglycaemic coma.
Conclusion:
Diabetic complications were the leading causes of endocrine-related admissions and mortality in this health facility. The co-morbidity of sepsis and hyperglycaemia may worsen mortality in patients who present with hyperglycaemic crises. Hence, evidence of infection should be sought early in such patients and appropriate therapy instituted.
doi:10.4103/0300-1652.119651
PMCID: PMC3821227  PMID: 24249952
Admissions; diabetes; endocrine-related diseases; hyperglycaemia; hypoglycaemia emergency; mortality
2.  Paradoxical effects of streptozotocin-induced diabetes on endothelial dysfunction in stroke-prone spontaneously hypertensive rats 
The Journal of Physiology  2011;589(21):5153-5165.
Non-technical summary
Elevated blood glucose is generally regarded as one of the risk factors that lead to coronary heart disease in patients with type 2 diabetes. However, our studies show that after inducing short-term damage, high blood glucose subsequently provides paradoxical protection for vessel function of animals with high blood pressure. Vessels can adapt to sustained high blood glucose and produce different stress proteins to counteract, to some extent, the damage brought about by hypertension. The results help us understand part of the basis for vessel adaptation in diabetes. The implication for treatment of diabetes is that if the patients have long-standing diabetes and established cardiovascular disease, the target of blood glucose lowering should be less stringent and reached gradually to avoid abrupt cancellation of the pre-existing adaptations.
Abstract
Although both diabetes and hypertension are risk factors for cardiovascular disease, the role of hyperglycaemia per se in endothelial dysfunction is controversial. This study was designed to examine whether hyperglycaemia, or streptozotocin-induced diabetes, could aggravate endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHRSP). Hyperglycaemia was induced by streptozotocin in 2-month-old SHRSP and age-matched normotensive Wistar–Kyoto (WKY) rats. The aorta was isolated 8 weeks after induction of hyperglycaemia to record its function and to examine its morphology with transmission electron microscopy. Endothelial/inducible nitric oxide synthase (eNOS/iNOS) and inducible/constitutive haem oxygenase (HO-1/HO-2) levels were determined with Western blotting. Aortic endothelial function and production of reactive oxygen species and nitric oxide were assayed after incubation in vitro in hyperglycaemic, hyperosmolar solution. Streptozotocin-induced diabetes of 8 weeks duration did not result in endothelial dysfunction in normotensive WKY rats. In contrast, hyperglycaemic WKY rats showed significantly enhanced endothelium-dependent vasodilatation, which was abrogated by simultaneous blocking of NOS and HO. The enhanced vasodilatation was associated with elevation of vascular eNOS and HO-1. Significant endothelial dysfunction and massive macrophage–monocyte infiltration were found in SHRSP aorta (the ratio of the number of macrophages to endothelial cells in the intima, expressed as a percentage, was 20.9 ± 2.8% in SHRSP versus 1.9 ± 0.5% in WKY rats, P < 0.01), which was attenuated significantly in hyperglycaemic SHRSP (11.3 ± 1.6%, P < 0.01 versus SHRSP). Acute hyperglycaemia (10 min) aggravated endothelial dysfunction in SHRSP, with a marked increase in intracellular reactive oxygen species and NO production. Sustained in vitro incubation in hyperglycaemic/hyperosmolar conditions (addition of an extra 50 mmol L−1 of glucose or mannitol to the usual buffer, to produce a final osmolarity of 350 mosmol L−1) for 5 h enhanced endothelium-dependent vasodilatation, with elevated vessel NO production and upregulation of eNOS/HO-1 proteins. Sustained hyperglycaemia does not aggravate endothelial dysfunction and macrophage infiltration in SHRSP. Hyperglycaemia/hyperosmolarity-induced upregulation of eNOS and HO-1 may play a role in this paradoxical adaptation of endothelial function.
doi:10.1113/jphysiol.2011.213686
PMCID: PMC3225671  PMID: 21930604
3.  Paradoxical effects of streptozotocin-induced diabetes on endothelial dysfunction in stroke-prone spontaneously hypertensive rats 
The Journal of Physiology  2011;589(Pt 21):5153-5165.
Non-technical summary
Elevated blood glucose is generally regarded as one of the risk factors that lead to coronary heart disease in patients with type 2 diabetes. However, our studies show that after inducing short-term damage, high blood glucose subsequently provides paradoxical protection for vessel function of animals with high blood pressure. Vessels can adapt to sustained high blood glucose and produce different stress proteins to counteract, to some extent, the damage brought about by hypertension. The results help us understand part of the basis for vessel adaptation in diabetes. The implication for treatment of diabetes is that if the patients have long-standing diabetes and established cardiovascular disease, the target of blood glucose lowering should be less stringent and reached gradually to avoid abrupt cancellation of the pre-existing adaptations.
Abstract
Although both diabetes and hypertension are risk factors for cardiovascular disease, the role of hyperglycaemia per se in endothelial dysfunction is controversial. This study was designed to examine whether hyperglycaemia, or streptozotocin-induced diabetes, could aggravate endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHRSP). Hyperglycaemia was induced by streptozotocin in 2-month-old SHRSP and age-matched normotensive Wistar–Kyoto (WKY) rats. The aorta was isolated 8 weeks after induction of hyperglycaemia to record its function and to examine its morphology with transmission electron microscopy. Endothelial/inducible nitric oxide synthase (eNOS/iNOS) and inducible/constitutive haem oxygenase (HO-1/HO-2) levels were determined with Western blotting. Aortic endothelial function and production of reactive oxygen species and nitric oxide were assayed after incubation in vitro in hyperglycaemic, hyperosmolar solution. Streptozotocin-induced diabetes of 8 weeks duration did not result in endothelial dysfunction in normotensive WKY rats. In contrast, hyperglycaemic WKY rats showed significantly enhanced endothelium-dependent vasodilatation, which was abrogated by simultaneous blocking of NOS and HO. The enhanced vasodilatation was associated with elevation of vascular eNOS and HO-1. Significant endothelial dysfunction and massive macrophage–monocyte infiltration were found in SHRSP aorta (the ratio of the number of macrophages to endothelial cells in the intima, expressed as a percentage, was 20.9 ± 2.8% in SHRSP versus 1.9 ± 0.5% in WKY rats, P < 0.01), which was attenuated significantly in hyperglycaemic SHRSP (11.3 ± 1.6%, P < 0.01 versus SHRSP). Acute hyperglycaemia (10 min) aggravated endothelial dysfunction in SHRSP, with a marked increase in intracellular reactive oxygen species and NO production. Sustained in vitro incubation in hyperglycaemic/hyperosmolar conditions (addition of an extra 50 mmol L−1 of glucose or mannitol to the usual buffer, to produce a final osmolarity of 350 mosmol L−1) for 5 h enhanced endothelium-dependent vasodilatation, with elevated vessel NO production and upregulation of eNOS/HO-1 proteins. Sustained hyperglycaemia does not aggravate endothelial dysfunction and macrophage infiltration in SHRSP. Hyperglycaemia/hyperosmolarity-induced upregulation of eNOS and HO-1 may play a role in this paradoxical adaptation of endothelial function.
doi:10.1113/jphysiol.2011.213686
PMCID: PMC3225671  PMID: 21930604
4.  New onset diabetes complicated by haemolysis and rhabdomyolysis: a case report and review of the literature 
Introduction
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.
Conclusion
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.
doi:10.1186/1752-1947-2-159
PMCID: PMC2440389  PMID: 18485212
5.  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.
Aims/hypothesis
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.
Methods
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.
Results
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.
Conclusions/interpretation
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.
doi:10.1007/s00125-008-1057-1
PMCID: PMC2719841  PMID: 18563383
Akita; Humanised mice; Insulin; Islet transplantation; NOD mice
6.  Prevalence, Predictors and Prognosis of Post-Stroke Hyperglycaemia in Acute Stroke Trials: Individual Patient Data Pooled Analysis from the Virtual International Stroke Trials Archive (VISTA) 
Background
Post-stroke hyperglycaemia (PSH) is associated with higher mortality and dependence, but further data on predictors of PSH and its evolution over time are required. We examined the prevalence, predictors, and prognosis of acute PSH using data from well-characterised clinical trials in the VISTA database.
Methods
Data were extracted for individual participants enrolled <24 h after stroke with ≥1 blood glucose readings documented. PSH was defined as glucose >7.0 mmol/l. Outcome measures were: (1) prevalence of PSH; (2) predictors of PSH by binary logistic regression; (3) mortality, and (4) favourable functional outcome [modified Rankin Scale (mRS) score <2] at day 90.
Results
For 2,649 subjects treated at a median 5.5 h after admission, PSH was present in 1,126 (42.6%, 95% CI 40.7–44.5) on admission and within the first 48 h in 1,421 (53.7%, 95% CI 51.8–55.6). PSH developed between 24 and 48 h in 19.4% (95% CI 17.5–21.4) of initially normoglycaemic subjects. Admission and 48-hour PSH were predicted predominantly by a history of diabetes (for admission PSH: OR 7.40, 95% CI 5.60–9.79) and less clearly by stroke severity. Favourable outcome (mRS <2) at day 90 was less likely with PSH within the first 48 h, advanced age, and higher NIHSS score, and more likely with recombinant tissue plasminogen activator treatment.
Conclusions
Over 40% of ischaemic stroke patients are hyperglycaemic on admission, and 20% of those who are initially normoglycaemic develop hyperglycaemia within 48 h. Diabetes is the strongest predictor of acute hyperglycaemia. Hyperglycaemia within the first 48 h is independently associated with higher mortality and poorer functional outcome, with an absolute increase of 12.9%.
doi:10.1159/000324319
PMCID: PMC3343756  PMID: 22566979
Acute stroke management; Glucose; Hyperglycaemia; Stroke outcome
7.  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.
Aims
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.
Methods
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).
Results
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.
Conclusions
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)
doi:10.1111/j.1464-5491.2007.02348.x
PMCID: PMC2268957  PMID: 18290856
cytokines; hyperglycaemia; hyperinsulinaemia; mRNA; neutrophils
8.  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.
doi:10.1136/jech.56.9.707
PMCID: PMC1732251  PMID: 12177090
9.  Crisis intervention for people with severe mental illnesses 
Background
A particularly difficult challenge for community treatment of people with serious mental illnesses is the delivery of an acceptable level of care during the acute phases of severe mental illness. Crisis intervention models of care were developed as a possible solution.
Objectives
To review the effects of crisis intervention models for anyone with serious mental illness experiencing an acute episode, compared with ‘standard care’.
Search methods
We updated the 1998, 2003 and 2006 searches with a search of the Cochrane Schizophrenia Group’s Register of trials (2010) which is based on regular searches of CINAHL, EMBASE, MEDLINE, and PsycINFO.
Selection criteria
We included all randomised controlled trials of crisis intervention models versus standard care for people with severe mental illnesses.
Data collection and analysis
We independently extracted data from these trials and we estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We assumed that people who left early from a trial had no improvement.
Main results
Three new studies have been found since the last review in 2006 to add to the five studies already included in this review. None of the previously included studies investigated crisis intervention alone; all used a form of home care for acutely ill people, which included elements of crisis intervention. However, one of the new studies focuses purely on crisis intervention as provided by Crisis Resolution Home Teams within the UK; the two other new studies investigated crisis houses i.e. residential alternatives to hospitalisation providing home-like environments.
Crisis intervention appears to reduce repeat admissions to hospital after the initial ‘index’ crises investigated in the included studies, this was particularly so for mobile crisis teams supporting patients in their own homes.
Crisis intervention reduces the number of people leaving the study early, reduces family burden, is a more satisfactory form of care for both patients and families and at three months after crisis, mental state is superior to standard care. We found no differences in death outcomes. Some studies found crisis interventions to be more cost effective than hospital care but all numerical data were either skewed or unusable. No data on staff satisfaction, carer input, complications with medication or number of relapses were available.
Authors’ conclusions
Care based on crisis intervention principles, with or without an ongoing home care package, appears to be a viable and acceptable way of treating people with serious mental illnesses. If this approach is to be widely implemented it would seem that more evaluative studies are still needed.
doi:10.1002/14651858.CD001087.pub4
PMCID: PMC4204394  PMID: 22592673
Caregivers [psychology]; Crisis Intervention [*methods]; Mental Disorders [psychology; *therapy]; Randomized Controlled Trials as Topic; Humans
10.  Clinical features, predictive factors and outcome of hyperglycaemic emergencies in a developing country 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1472-6823-9-9
PMCID: PMC2661082  PMID: 19272167
11.  Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations 
Background
Elevated non-esterified fatty acids (NEFA) concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL), 105 and 135 days gestational age (dGA, term 147+/- 3 days).
Methods
The plasma concentrations of insulin, growth hormone (GH) and ovine placental lactogen (oPL) were determined by double antibody radioimmunoassay. Insulin responsiveness to glucose was measured using bolus injection and hyperglycaemic clamp techniques in 15 non-pregnant, non-lactating ewes and in nine pregnant ewes at 105 dGA and near term at 135 dGA. Plasma samples were also collected for hormone determination. In addition to bolus injection glucose and insulin Area Under Curve calculations, the Mean Plasma Glucose Increment, Glucose Infusion Rate and Mean Plasma Insulin Increment and Area Under Curve were determined for the hyperglycaemic clamp procedures. Statistical analysis of data was conducted with Students t-tests, repeated measures ANOVA and 2-way ANOVA.
Results
Maternal growth hormone, placental lactogen and NEFA concentrations increased, while basal glucose and insulin concentrations declined with advancing gestation. At 135 dGA following bolus glucose injections, peak insulin concentrations and insulin area under curve (AUC) profiles were significantly reduced in pregnant ewes compared with NPNL control ewes (p < 0.001 and P < 0.001, respectively). In hyperglycaemic clamp studies, while maintaining glucose levels not different from NPNL ewes, pregnant ewes displayed significantly reduced insulin responses and a maintained depressed insulin secretion. In NPNL ewes, 105 and 135 dGA ewes, the Glucose Infusion Rate (GIR) was constant at approximately 5.8 mg glucose/kg/min during the last 40 minutes of the hyperglycaemic clamp and the Mean Plasma Insulin Increment (MPII) was only significantly (p < 0.001) greater in NPNL ewes. Following the clamp, NEFA concentrations were reduced by approximately 60% of pre-clamp levels in all groups, though a blunted and suppressed insulin response was maintained in 105 and 135 dGA ewes.
Conclusions
Results suggest that despite an acute suppression of circulating NEFA concentrations during pregnancy, the associated steroids and hormones of pregnancy and possibly NEFA metabolism, may act to maintain a reduced insulin output, thereby sparing glucose for non-insulin dependent placental uptake and ultimately, fetal requirements.
doi:10.1186/1477-7827-2-64
PMCID: PMC519029  PMID: 15352999
12.  Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state 
Obstructive sleep apnoea (OSA) is a cardio-metabolic disorder. Whether metabolic syndrome (MS), insulin resistance (IR) and albuminuria are independently associated with OSA is unclear, but defining the interactions between OSA and various cardiovascular (CV) risk factors independent of obesity facilitates the development of therapeutic strategies to mitigate their increased CV risks. We prospectively recruited 38 subjects with OSA and 41 controls. Anthropometric measurements, glucose, lipids, insulin and blood pressure (BP) were measured after an overnight fast. IR state was defined as homeostasis model assessment (HOMA) value >3.99 and MS diagnosed according to the International Diabetes Federation (IDF) criteria. Subjects with OSA were more obese, more insulin resistant, more hyperglycaemic, had higher Epworth score (measure of day time somnolence) and systolic blood pressure levels. The prevalence of MS was higher in OSA compared with non-OSA subjects (74% vs 24%, p < 0.001). The prevalence of microalbuminuria in both groups was negligible. Logistic regression adjusted for age, BMI and smoking showed that the patient with OSA was 5.9 (95% CI 2.0–17.6) times more likely to have MS than non-OSA patient. Triglyceride (p = 0.031), glucose (0.023) and Epworth score (0.003) values were independently associated with OSA after adjusting for BMI and other covariates whilst IR status was found not to be significant. Using the ROC curve analysis, we found that a waist circumference of >103 cm would predict MS in patients with OSA at 75–78% sensitivity and 61–64% specificity. The agreement between MS and IR state in this cohort is poor. Thus, OSA is associated with MS independent of obesity predominantly due to increased triglyceride, glucose and Epworth score values but not IR or microalbuminuria status. This observation suggests an alternative pathogenic factor mediating the increased cardiovascular risk in patients with OSA and MS, other than that due to IR. The independent link between Epworth score and MS in patients with OSA implicates the role of daytime sleepiness and chronic hypoxia as a potential mediator. Given the discordant between MS and IR state, measurement of waist is useful for predicting mainly MS but not insulin resistance status in patients with OSA. Appropriate pharmacological intervention targeting these independent factors is important in reducing the increased CV risks among patients with OSA.
doi:10.1186/1475-2840-5-22
PMCID: PMC1636630  PMID: 17078884
13.  Metformin-mediated growth inhibition involves suppression of the IGF-I receptor signalling pathway in human pancreatic cancer cells 
BMC Cancer  2013;13:235.
Background
Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated.
Methods
The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro.
Results
Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPKThr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPKSer485 phosphorylation and impaired AMPKThr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin.
Conclusion
Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPKThr172 activation and suppression of the insulin/IGF signalling pathways. However, hyperglycaemic conditions enhance the insulin/IGF-I responses resulting in an altered AMPK activation profile and prevent metformin from fully switching off the growth promoting signals in pancreatic cancer cells.
doi:10.1186/1471-2407-13-235
PMCID: PMC3661399  PMID: 23663483
Pancreatic cancer; Type 2 diabetes mellitus; Hyperglycaemia; Metformin; Insulin-like growth factor (IGF); Signalling
14.  Angiopoietin 2 Alters Pancreatic Vascularization in Diabetic Conditions 
PLoS ONE  2012;7(1):e29438.
Aims/hypothesis
Islet vascularization, by controlling beta-cell mass expansion in response to increased insulin demand, is implicated in the progression to glucose intolerance and type 2 diabetes. We investigated how hyperglycaemia impairs expansion and differentiation of the growing pancreas. We have grafted xenogenic (avian) embryonic pancreas in severe combined immuno-deficient (SCID) mouse and analyzed endocrine and endothelial development in hyperglycaemic compared to normoglycaemic conditions.
Methods
14 dpi chicken pancreases were grafted under the kidney capsule of normoglycaemic or hyperglycaemic, streptozotocin-induced, SCID mice and analyzed two weeks later. Vascularization was analyzed both quantitatively and qualitatively using either in situ hybridization with both mouse- and chick-specific RNA probes for VEGFR2 or immunohistochemistry with an antibody to nestin, a marker of endothelial cells that is specific for murine cells. To inhibit angiopoietin 2 (Ang2), SCID mice were treated with 4 mg/kg IP L1–10 twice/week.
Results
In normoglycaemic condition, chicken-derived endocrine and exocrine cells developed well and intragraft vessels were lined with mouse endothelial cells. When pancreases were grafted in hyperglycaemic mice, growth and differentiation of the graft were altered and we observed endothelial discontinuities, large blood-filled spaces. Vessel density was decreased. These major vascular anomalies were associated with strong over-expression of chick-Ang2. To explore the possibility that Ang2 over-expression could be a key step in vascular disorganization induced by hyperglycaemia, we treated mice with L1–10, an Ang-2 specific inhibitor. Inhibition of Ang2 improved vascularization and beta-cell density.
Conclusions
This work highlighted an important role of Ang2 in pancreatic vascular defects induced by hyperglycaemia.
doi:10.1371/journal.pone.0029438
PMCID: PMC3260141  PMID: 22272235
15.  Gestational Diabetes Mellitus: Screening and Outcomes in Southern Italian Pregnant Women 
ISRN Endocrinology  2013;2013:387495.
Recent Italian guidelines exclude women <35 years old, without risk factors for gestational diabetes mellitus (GDM), from screening for GDM. To determine the effectiveness of these measures with respect to the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria, we evaluated 2,448 pregnant women retrospectively enrolled in Calabria, southern Italy. GDM was diagnosed following the IADPSG 2010 criteria. Among 538 women <35 years old, without risk factors, who would have not been tested according to the Italian guidelines, we diagnosed GDM in 171 (31.8%) pregnants (7.0% of total pregnants). Diagnosis was made at baseline (55.6%), 1 hour (39.8%), or 2 hours (4.7%) during OGTT. Despite of appropriate treatment, GDM represented a risk factor for cesarean section, polyhydramnios, increased birth weight, admission to neonatal intensive care units, and large for gestational age. These outcomes were similar to those observed in GDM women at high risk for GDM. In conclusion, Italian recommendations failed to identify 7.0% of women with GDM, when compared to IADPSG criteria. The risk for adverse hyperglycaemic-related outcomes is similar in low-risk and high-risk pregnants with GDM. To limit costs of GDM screening, our data suggest to restrict OGTT to two steps (baseline and 1 hour).
doi:10.1155/2013/387495
PMCID: PMC3777200  PMID: 24093064
16.  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.
doi:10.11613/BM.2013.002
PMCID: PMC3900087  PMID: 23457760
gestational diabetes; IADPSG criteria; clinical laboratory techniques
17.  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
18.  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.
Aims/hypothesis
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.
Methods
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.
Results
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.
Conclusions/interpretation
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.
doi:10.1007/s00125-008-1044-6
PMCID: PMC2542900  PMID: 18493734
Animal; Complement; Mannose-binding lectin; Type 1 diabetes
19.  Global microRNA expression profiles in insulin target tissues in a spontaneous rat model of type 2 diabetes 
Diabetologia  2010;53(6):1099-1109.
Aims/hypothesis
MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global microRNA expression in insulin target tissues from three inbred rat strains that differ in diabetes susceptibility.
Methods
Using microarrays, we measured the expression of 283 microRNAs in adipose, liver and muscle tissue from hyperglycaemic (Goto–Kakizaki), intermediate glycaemic (Wistar Kyoto) and normoglycaemic (Brown Norway) rats (n = 5 for each strain). Expression was compared across strains and validated using quantitative RT-PCR. Furthermore, microRNA expression variation in adipose tissue was investigated in 3T3-L1 adipocytes exposed to hyperglycaemic conditions.
Results
We found 29 significantly differentiated microRNAs (padjusted < 0.05): nine in adipose tissue, 18 in liver and two in muscle. Of these, five microRNAs had expression patterns that correlated with the strain-specific glycaemic phenotype. MiR-222 (padjusted = 0.0005) and miR-27a (padjusted = 0.006) were upregulated in adipose tissue; miR-195 (padjusted = 0.006) and miR-103 (padjusted = 0.04) were upregulated in liver; and miR-10b (padjusted = 0.004) was downregulated in muscle. Exposure of 3T3-L1 adipocytes to increased glucose concentration upregulated the expression of miR-222 (p = 0.008), miR-27a (p = 0.02) and the previously reported miR-29a (p = 0.02). Predicted target genes of these differentially expressed microRNAs are involved in pathways relevant to type 2 diabetes.
Conclusion
The expression patterns of miR-222, miR-27a, miR-195, miR-103 and miR-10b varied with hyperglycaemia, suggesting a role for these microRNAs in the pathophysiology of type 2 diabetes, as modelled by the Gyoto–Kakizaki rat. We observed similar patterns of expression of miR-222, miR-27a and miR-29a in adipocytes as a response to increased glucose levels, which supports our hypothesis that altered expression of microRNAs accompanies primary events related to the pathogenesis of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-010-1667-2) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-010-1667-2
PMCID: PMC2860560  PMID: 20198361
Expression; MicroRNA; Murine diabetes model
20.  Validating self-report of diabetes use by participants in the 45 and up study: a record linkage study 
Background
Prevalence studies usually depend on self-report of disease status in survey data or administrative data collections and may over- or under-estimate disease prevalence. The establishment of a linked data collection provided an opportunity to explore the accuracy and completeness of capture of information about diabetes in survey and administrative data collections.
Methods
Baseline questionnaire data at recruitment to the 45 and Up Study was obtained for 266,848 adults aged 45 years and over sampled from New South Wales, Australia in 2006–2009, and linked to administrative data about hospitalisation from the Admitted Patient Data Collection (APDC) for 2000–2009, claims for medical services (MBS) and pharmaceuticals (PBS) from Medicare Australia data for 2004–2009. Diabetes status was determined from response to a question ‘Has a doctor EVER told you that you have diabetes’ (n = 23,981) and augmented by examination of free text fields about diagnosis (n = 119) or use of insulin (n = 58). These data were used to identify the sub-group with type 1 diabetes. We explored the agreement between self-report of diabetes, identification of diabetes diagnostic codes in APDC data, claims for glycosylated haemoglobin (HbA1c) in MBS data, and claims for dispensed medication (oral hyperglycaemic agents and insulin) in PBS data.
Results
Most participants with diabetes were identified in APDC data if admitted to hospital (79.3%), in MBS data with at least one claim for HbA1c testing (84.7%; 73.4% if 2 tests claimed) or in PBS data through claim for diabetes medication (71.4%). Using these alternate data collections as an imperfect ‘gold standard’ we calculated sensitivities of 83.7% for APDC, 63.9% (80.5% for two tests) for MBS, and 96.6% for PBS data and specificities of 97.7%, 98.4% and 97.1% respectively. The lower sensitivity for HbA1c may reflect the use of this test to screen for diabetes suggesting that it is less useful in identifying people with diabetes without additional information. Kappa values were 0.80, 0.70 and 0.80 for APDC, MBS and PBS respectively reflecting the large population sample under consideration. Compared to APDC, there was poor agreement about identifying type 1 diabetes status.
Conclusions
Self-report of diagnosis augmented with free text data indicating diabetes as a chronic condition and/or use of insulin among medications used was able to identify participants with diabetes with high sensitivity and specificity compared to available administrative data collections.
doi:10.1186/1472-6963-13-481
PMCID: PMC3893423  PMID: 24245780
Primary health care; Cohort studies; Diabetes mellitus; Record linkage; Health service data; Quality of health care; Validation study; Sensitivity and specificity; Older age; English language
21.  Anti hyperglycaemic study of natural inhibitors for Insulin receptor 
Bioinformation  2012;8(24):1195-1201.
Diabetes is a metabolic disorder associated with either improper functioning of the beta-cells or wherein cells fail to use insulin properly. Insulin, the principal hormone regulates uptake of glucose from the blood into most of the cells except central nervous system. Therefore, deficiency of insulin or the insensitivity of its receptors plays a key role in all forms of diabetes. In the present work, attempt has been made to find out plant sources which show anti hyperglycaemic activity (AhG) (i.e. compounds that bring down the blood glucose level in the body). Ayurvedic plants showing AhG activity formed the basis of our study by using the platform of Computer Aided Drug Designing (CADD). Among 600 plants showing AhG activity, 500 compounds were selected and screened, out of which 243 compounds showed drug likeness property that can be used as therapeutic ligand/drug. Initial screening of such compounds was done based on their drug likeness or biochemical properties. Dynamic interaction of these molecules was captured through Protein-Ligand study. It also gave an insight of the binding pockets involved. Bench marking of all the parameters were done using the diabetic inhibitor drug, Glipizide. Pharmacokinetic studies of the compounds such as Aloins, Capparisine, Funiculosin and Rhein exhibited less toxicity on various levels of the body. As a conclusion these ligands can lay a foundation for a better anti-diabetic therapy.
Abbreviations
AhG - Anti hyperglycaemic, CADD - Computer Aided Drug Designing.
doi:10.6026/97320630081195
PMCID: PMC3530871  PMID: 23275719
Anti hyperglycaemic property; Protein-ligand interactions; Computer aided drug designing; Diabetic inhibitor; Pharmacokinetic parameters
22.  Glucose tolerance in patients with cystic fibrosis: five year prospective study. 
BMJ : British Medical Journal  1995;311(7006):655-659.
OBJECTIVES--To study prevalence and incidence of diabetes mellitus in patients with cystic fibrosis. DESIGN--Five year prospective study with annual oral glucose tolerance tests. SETTING--CF Center Copenhagen, Denmark. SUBJECTS--191 patients with cystic fibrosis aged above 2 years. MAIN OUTCOME MEASURES--Glucose tolerance, plasma glucose concentrations after fasting and after glucose loading, and haemoglobin A1c levels. RESULTS--Prevalence of diabetes increased from 11% (n = 21) to 24% (n = 46) during study, with annual age dependent incidence of 4-9%. Diabetes was diagnosed at median age of 21 (range 3-40). At diagnosis of diabetes, symptoms of hyperglycaemia were present in 33% of patients, fasting hyperglycaemia (> or = 7.8 mmol/l) was seen in 16%, and increased haemoglobin A1c levels (> 6.4%) were seen in 16%. Impaired glucose tolerance implied higher risk for development of diabetes than normal glucose tolerance (odds ratio 5.6). In 58% of cases with impaired glucose tolerance, however, glucose tolerance was normal at next annual test. Normal glucose tolerance was found in only 37% of patients at all five tests. Within this group of patients, median plasma glucose concentrations after fasting and after glucose loading and haemoglobin A1c levels increased by 6-8% during study. CONCLUSIONS--Prevalence and incidence of diabetes in cystic fibrosis patients was high and increased with age. Since hyperglycaemic symptoms, fasting hyperglycaemia, and increased levels of glycated haemoglobin did not reliably identify diabetes mellitus, we recommend annual oral glucose tolerance tests in all cystic fibrosis patients aged over 10 years.
PMCID: PMC2551427  PMID: 7549632
23.  Consequences of Advanced Glycation End Products Accumulation in Chronic Kidney Disease and Clinical Usefulness of Their Assessment Using a Non-invasive Technique – Skin Autofluorescence 
Mædica  2011;6(4):298-307.
ABSTRACT
Accelerated formation and accumulation of advanced glycation end-products occur under circumstances of increased supply of substrates such as hyperglycaemic or oxidative stress and in age-related and chronic diseases like diabetes mellitus, chronic renal failure, neurodegenerative diseases, osteoarthritis and also non-diabetic atherosclerosis and chronic heart failure. Advanced glycation end-products accumulation occurs especially on long-lived proteins such as collagen in the skin and in vascular basement membranes leading to vascular damage. Adequate renal clearance capacity is an important factor in the effective removal of advanced glycation end-products. The Autofluorescence Reader was developed as a marker, representative for tissue advanced glycation end-products accumulation, easily applicable in a clinical setting, initially for predicting diabetes related complications. Studies have already shown a relationship between skin autofluorescence and diabetes complications, as well as its predictive value for total and cardiovascular mortality in type 2 diabetes. Moreover skin autofluorescence was demonstrated to be superior to Haemoglobin A1c and other conventional risk factors. Advanced glycation end-products have been proposed as a novel factor involved in the development and progression of chronic heart failure. Assessment of advanced glycation end-products accumulation in end-stage renal disease and undergoing renal replacement therapies patients has become of great importance. Cardiovascular and connective tissue disorders are very common in patients with end-stage renal disease, and the accumulation of advanced glycation end-products is significantly increased in these patients. Mortality is markedly increased in patients with decreased kidney function, particularly in patients with end-stage renal disease. Skin advanced glycation end-products levels are strong predictors of survival in haemodialysis patients independent of other established risk factors. The Autofluorescence Reader may be useful as a clinical tool for rapid assessment of risk for advanced glycation end-products related long-term complications, not only in diabetes, but in other conditions associated with advanced glycation end-products accumulation as well.
PMCID: PMC3391948  PMID: 22879845
advanced glycation end-products; skin autofluorescence; metabolic stess; chronic kidney disease
24.  Anti-hyperglycaemic activity of swietenia macrophylla king (meliaceae) seed extracts in normoglycaemic rats undergoing glucose tolerance tests 
Chinese Medicine  2013;8:11.
Background
Swietenia macrophylla King (Meliaceae) is used to treat diabetes mellitus in Malaysia. This study aims to evaluate the anti-hyperglycaemic potential of petroleum ether (PE), chloroform (CE) and methanol (ME) extracts of S. macrophylla seeds, in normoglycaemic and streptozotocin (STZ)-induced diabetic rats.
Methods
Following treatment of normoglycaemic rats with S. macrophylla seed extracts, hypoglycaemic and intraperitoneal glucose tolerance tests (IPGTT) were performed, and blood glucose concentrations were measured. Similarly, glucose concentrations were measured after 1 and 14 days of extract treatment of STZ-induced diabetic rats. Glucose absorption by isolated everted intestine and glucose uptake by isolated abdominal muscle were tested after treatment with seed extracts. Gas chromatography mass spectrometry (GC-MS) analysis was performed on PE of S. macrophylla seeds to identify the compounds responsible for its activity.
Results
None of the extracts had a significant effect on the blood glucose levels of 60 randomly selected normoglycaemic (normal) and diabetic rats undergoing hypoglycaemic tests. PE, however, significantly reduced blood glucose levels in 30 randomly selected normoglycaemic rats undergoing IPGTT tests 30–120 minutes after glucose administration. Repeated doses of 1000 mg/kg and 500 mg/kg PE to STZ-induced diabetic rats for 14 days did not reduce blood glucose levels significantly. PE did not significantly reduced the intestinal absorption of glucose, but significantly increased glucose uptake by abdominal muscle in the absence or presence of insulin. GC-MS analysis indicated that diterpenes, triterpenoids, fatty acid methyl esters, aldehydes and phytosterols may be responsible for the glucose lowering effects of PE.
Conclusion
PE extracts of S. macrophylla seeds showed anti-hyperglycaemic activity on IPGTTs . GC-MS analysis on the PE revealed that several compounds, including fucosterol and β-sitosterol, may be responsible for these anti-hyperglycaemic properties.
doi:10.1186/1749-8546-8-11
PMCID: PMC3668191  PMID: 23684219
25.  Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms 
Diabetologia  2007;50(12):2443-2450.
Aims/hypothesis
Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes and reduced insulin secretion. The transcription factor TCF7L2 is an essential factor for glucagon-like peptide-1 (GLP-1) secretion from intestinal L cells. We studied whether a defect in the enteroinsular axis contributes to impaired insulin secretion in carriers of TCF7L2 polymorphisms.
Methods
We genotyped 1,110 non-diabetic German participants for five single nucleotide polymorphisms in TCF7L2. All participants underwent an OGTT; GLP-1 secretion was measured in 155 participants. In 210 participants, an IVGTT combined with a hyperinsulinaemic–euglycaemic clamp was performed. In another 160 participants from the Netherlands and 73 from Germany, a hyperglycaemic clamp (10 mmol/l) was performed. In 73 German participants this clamp was combined with a GLP-1 infusion and an arginine bolus.
Results
The OGTT data confirmed that variants in TCF7L2 are associated with reduced insulin secretion. In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 concentrations during the OGTT were not influenced by the TCF7L2 variants. However, GLP-1-infusion combined with a hyperglycaemic clamp showed a significant reduction in GLP-1-induced insulin secretion in carriers of the risk allele in two variants (rs7903146, rs12255372, p < 0.02).
Conclusions/interpretation
Variants of TCF7L2 specifically impair GLP-1-induced insulin secretion. This seems to be rather the result of a functional defect in the GLP-1 signalling in beta cells than a reduction in GLP-1 secretion. This defect might explain the impaired insulin secretion in carriers of the risk alleles and confers the increased risk of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-007-0753-6) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-007-0753-6
PMCID: PMC2063563  PMID: 17661009
GLP-1; Insulin secretion; Polymorphism; TCF7L2

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