Novel approaches to the treatment of hyperglycaemia in type 2 diabetes mellitus

Control of hyperglycaemia is a fundamental therapeutic goal in patients with type 2 diabetes. The progressive nature of β‐cell dysfunction in type 2 diabetes leads to the need for escalating anti‐hyperglycaemic treatment, including insulin, in most patients. Given the prevalence of complications such as weight gain and hypoglycaemia associated with traditional anti‐hyperglycaemic agents (AHA), including sulphonylureas and insulin, it is unsurprising that recent years have seen the development of novel agents to treat hyperglycaemia. With increasing evidence supporting the need for a multi‐faceted approach to the prevention of adverse cardiovascular events in people with type 2 diabetes, a patient‐centred and individualised management strategy addressing lifestyle, cardiovascular risk factor modification and glycaemic control remains critical in improving outcomes in these patients.     

The advantages and disadvantages of a 'herbal' medicine in a patient with diabetes mellitus: a case report.

BACKGROUND: Patient-initiated alternative treatments in the management of chronic conditions are common and increasing in the United Kingdom. To date, there have been no reports of herbal medicine use alone in the management of diabetes mellitus. We report here the case of a man who attained excellent glycaemic control using a 'herbal' medicine and reveal how important it was to identify the products of active constituents. CASE REPORT: A 48-year-old man attending our clinic in Tooting, South London with known Type 2 diabetes, with evidence of both micro- and macro-vascular diabetes-related complications, was poorly controlled despite a drug regimen consisting of oral metformin and twice daily insulin. He went to India for at least 1 year and on returning to the clinic had excellent glycaemic control off all diabetic medication. While away he had started himself on a regimen of three different 'herbal' balls. Samples of blood were found to contain chlorpropamide in a therapeutic concentration; chlorpropamide was also found in one of the balls. He has been counselled on the potential risks associated with chlorpropamide and his treatment reverted to a more conventional treatment regimen. CONCLUSIONS: General practitioners and hospital physicians should be alert to those patients returning from abroad on effective 'herbal' medications that these may in fact contain an active ingredient.     

Increasing prevalence of diabetes mellitus in Oman.

AIMS: To determine the prevalence of diabetes mellitus and impaired fasting glucose by age, gender, and by region and compare results with the 1991 survey; and estimate previously undiagnosed diabetes mellitus in the Omani population. METHODS: Cross-sectional survey containing a probability random sample of 5838 Omani adults aged >or= 20 years. Diabetes and impaired fasting glucose (IFG) were assessed by fasting venous plasma glucose using 1999 World Health Organization's diagnostic criteria (normoglycaemia < 6.1 mmol/l, IFG >or= 6.1 but < 7 mmol/l,and diabetes >or= 7 mmol/l). The 1991 survey was reanalysed using the same diagnostic criteria, and results were compared. RESULTS: In 2000, the age-adjusted prevalence of diabetes among Omanis aged 30-64 years reached 16.1% (95% confidence interval (CI) 14.7-17.4) compared with 12.2% (95% CI11.0-13.4) in 1991. IFG was found among 7.1% (95% CI6.2-8.1) of males and 5.1% (95% CI 4.4-6.0) of females. Generally, diabetes was more common in urban then rural regions. Only one-third of diabetic subjects knew that they had diabetes. Nearly half of the study population had a body mass index > 25 kg/m2. CONCLUSIONS: The prevalence of diabetes is high in Oman and has increased over the past decade. The high rate of abnormal fasting glucose together with high rates of overweight and obesity in the population make it likely that diabetes will continue to be a major health problem in Oman. Primary prevention programmes are urgently needed to counteract major risk factors that promote the development of diabetes.     

Pathophysiology of ketoacidosis in Type 2 diabetes mellitus.

AIMS: Despite an increasing number of reports of ketoacidosis in populations with Type 2 diabetes mellitus, the pathophysiology of the ketoacidosis in these patients is unclear. We therefore tested the roles of three possible mechanisms: elevated stress hormones, increased free fatty acids (FFA), and suppressed insulin secretion. METHODS: Forty-six patients who presented to the Emergency Department with decompensated diabetes (serum glucose > 22.2 mmol/l and/or ketoacid concentrations > or = 5 mmol/l), had blood sampled prior to insulin therapy. Three groups of subjects were studied: ketosis-prone Type 2 diabetes (KPDM2, n = 13) with ketoacidosis, non-ketosis-prone subjects with Type 2 diabetes (DM2, n = 15), and ketotic Type 1 diabetes (n = 18). RESULTS: All three groups had similar mean plasma glucose concentrations. The degree of ketoacidosis (plasma ketoacids, bicarbonate and anion gap) in Type 1 and 2 subjects was similar. Mean levels of counterregulatory hormones (glucagon, growth hormone, cortisol, epinephrine, norepinephrine), and FFA were not significantly different in DM2 and KPDM2 patients. In contrast, plasma C-peptide concentrations were approximately three-fold lower in KPDM2 vs. non-ketotic DM2 subjects (P = 0.0001). Type 1 ketotic subjects had significantly higher growth hormone (P = 0.024) and FFA (P < 0.002) and lower glucagon levels (P < 0.02) than DM2. CONCLUSIONS: At the time of hospital presentation, the predominant mechanism for ketosis in KPDM2 is likely to be greater insulinopenia.     

In-patient management of diabetes mellitus and patient satisfaction.

AIMS: To devise a system for assessing in-patient glycaemic control and care satisfaction in diabetic patients admitted to hospital for reasons other than their diabetes. METHODS: Consecutive January to March 2001 case-notes were reviewed. Admissions with acute metabolic complications, acute myocardial infarction and pregestational or gestational diabetes were excluded. Glycaemic control, frequency of blood monitoring and management of hyperglycaemia were recorded. The diabetes treatment satisfaction questionnaire was used to assess preadmission satisfaction with care. Post-admission a 12-stem questionnaire was used to assess satisfaction with in-patient diabetes management. RESULTS: Hypoglycaemia was common. Although none developed a hyperglycaemic emergency, high blood glucose was prevalent and, frequently, persistent hyperglycaemia or recurrent hypoglycaemia was not acted on appropriately. The overall score for in-patient satisfaction with treatment was fair (4.1 +/- 1.8 on a six-point scale; 6 = very satisfied and 1 = very dissatisfied). Scores were higher among patients on surgical wards than on medical wards (P = 0.008), but satisfaction did not vary when patients were stratified according to sex, age and mode of treatment. CONCLUSION: Current systems are not achieving satisfactory in-patient glycaemic control and there is poor satisfaction with medical in-patient diabetes care. Following changes intended to produce improvements, this assessment system can be used recurrently to monitor in-patient care and satisfaction.     

Complementary and alternative medicine in children with type 1 diabetes mellitus

Objective: Complementary and alternative medicine (CAM) is increasingly utilized in adults and children for treatment of various conditions. Studies on CAM in diabetes have mainly focused on the adult population and its application in children has not been well established. The aim of this study was to examine the prevalence and characteristics of CAM use in Turkish children with type 1 diabetes mellitus (T1DM). Methods: The information was acquired by a questionnaire completed by a face-to-face interview with the parents of children with T1DM. Results: A total of 195 subjects (mean age: 14.02±4.7 years; F/M: 103/92) were included in this survey. Use of CAM was reported in 85 subjects (43.6%). Herbal medicines were used in 64 subjects (75.3%). Sixty-nine subjects (81.2%) did not inform the diabetes specialist about CAM use. Thirty-eight subjects (44.7%) evaluated CAM as efficacious. Only 3 subjects (3.5%) interrupted the insulin injections to use CAM. No relationships were found between CAM use and parental education or insulin dose. There were significant correlations between CAM use and higher family income (p=0.027), urban residence (p=0.05), presence of complications (p=0.03), dissatisfaction with medical therapy (p=0.034) and prior CAM use among parents (p=0.001). Conclusion: CAM use is a frequent practice among diabetic children, which is usually not shared with their physicians and sometimes leads to cessation of medical treatment. Conflict of interest:None declared.     

Hyperproinsulinaemia and risk of Type 2 diabetes mellitus in women.

AIMS: Our objective was to examine prospectively the associations between fasting plasma proinsulin and the proinsulin/insulin ratio and the incidence of Type 2 diabetes in women. SUBJECTS AND METHODS: We designed a nested case-control study within the Nurses' Health Study, a cohort of 121,700 US women aged 30-55 years at study inception in 1976. Fasting plasma proinsulin, specific insulin and C-peptide levels were determined in 183 women with a new diagnosis of diabetes made after blood sampling between 1989 and 1990, and 369 control subjects without diabetes. RESULTS: After adjustment for age, body mass index, family history of diabetes and other potential confounders, including HbA1c, the odds ratios for diabetes associated with increasing quartiles of proinsulin were 1.00, 0.85, 2.49 and 5.73 (P for trend: < 0.001). Proinsulin remained significantly associated with diabetes risk after adjusting for C-peptide and specific insulin (multivariate odds ratios for quartiles: 1.00, 0.78, 1.94, 3.69; P for trend = 0.001). In addition, the proinsulin/insulin ratio was significantly associated with diabetes risk, controlling in multivariate analysis for C-peptide (odds ratios for extreme quartiles: 2.48; 95% CI: 1.14-5.41; P for trend = 0.005). CONCLUSIONS: These data suggest that proinsulin and the proinsulin/insulin ratio are strong independent predictors of diabetes risk, after adjustment for obesity and other potential confounders.     

Diabetes mellitus: influences on cancer risk

Diabetes mellitus and cancer are common conditions, and their co‐diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2–1.5‐fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non‐Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti‐diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre‐existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes. Copyright © 2014 John Wiley & Sons, Ltd.     

Diagnostic screening of NEUROD1 (MODY6) in subjects with MODY or gestational diabetes mellitus.

AIMS: Diagnostic screening of NEUROD1 in patients with maturity-onset diabetes of the young (MODY) without mutations in the known MODY-genes (MODYX) and in subjects diagnosed with gestational diabetes mellitus. METHODS: Direct sequencing of NEUROD1 was performed in (i) 73 probands with clinical MODY without mutations in hepatocyte nuclear factor (HNF)-4alpha (MODY1), glucokinase (MODY2) and hepatocyte nuclear factor (HNF)-1alpha (MODY3), and (ii) 51 subjects diagnosed with gestational diabetes. Control material consisted of 105 anonymous blood donors. RESULTS: Mean age at diagnosis of diabetes was 22 and 30 years in the MODYX patients and gestational diabetes mellitus subjects, respectively. Mean fasting blood glucose (9.6 +/- 4.3 vs. 5.7 +/- 1.0 mml/l) as well as glycosylated haemoglobin (8.2 +/- 2.4 vs. 6.0 +/- 0.6%) were higher in the MODYX patients than subjects with gestational diabetes. NEUROD1 mutations were not detected in our two study groups. Three previously reported polymorphisms were found: Ala45Thr, Pro197His and IVS1 -32 nt C>T. The amino acid substitution serine to cysteine in codon 29 (designated Ser29Cys) was detected in one out of 105 control subjects. As the control material consisted of anonymous blood donors, we were prevented from investigation of possible co-segregation between the sequence variant Ser29Cys and diabetes mellitus. CONCLUSIONS: As we found no NEUROD1 mutations, diagnostic screening for this gene is not warranted in Norwegian MODYX patients. Our study also suggests that NEUROD1 is not a candidate gene in gestational diabetes mellitus (GDM). The sequence variant Ser29Cys was identified in one anonymous DNA sample, but we were prevented from studying possible co-segregation with diabetes mellitus.     

Self-monitoring in Type 2 diabetes mellitus: a meta-analysis.

AIMS: Self-monitoring of blood or urine glucose is widely used by subjects with Type 2 diabetes mellitus. This study evaluated the effectiveness of the technique at improving blood glucose control through a systematic review and meta-analysis. METHODS: Randomized controlled trials were identified that compared the effects of blood or urine glucose monitoring with no self-monitoring, or blood glucose self-monitoring with urine glucose self-monitoring, on glycated haemoglobin as primary outcome in Type 2 diabetes. RESULTS: Eight reports were identified. These were rated for quality and data were abstracted. The mean (SD) quality score was 15.0 (1.69) on a scale ranging from 0 to 28. No study had sufficient power to detect differences in glycated haemoglobin (GHb) of less than 0.5%. One study was excluded because it was a cluster randomized trial of a complex intervention and one because fructosamine was used as the outcome measure. A meta-analysis was performed using data from four studies that compared blood or urine monitoring with no regular monitoring. The estimated reduction in GHb from monitoring was -0.25% (95% confidence interval -0.61 to 0.10%). Three studies that compared blood glucose monitoring with urine glucose monitoring were also combined. The estimated reduction in GHb from monitoring blood glucose rather than urine glucose was -0.03% (-0.52 to 0.47%). CONCLUSIONS: The results do not provide evidence for clinical effectiveness of an item of care with appreciable costs. Further work is needed to evaluate self-monitoring so that resources for diabetes care can be used more efficiently.     

Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus.

AIMS: The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines. SUBJECTS AND METHODS: Forty-two non-diabetic first-degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA-2 antibody). Follow-up for 9-11 years confirmed high vs. moderate diabetes risk in islet autoantibody-positive vs. -negative relatives. Cytokines and chemokines were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum concentrations of classic Th1-associated cytokines (IFN-gamma, IL-12, IL-18) or Th2/Treg-associated cytokines (IL-5, IL-10, IL-13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody-positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody-negative group. CONCLUSION: Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.     

Maturity‐onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus

Maturity‐onset diabetes of the young (MODY) is a form of diabetes classically characterized as having autosomal dominant inheritance, onset before the age of 25 years in at least one family member and partly preserved pancreatic β‐cell function. The 14 responsible genes are reported to be MODY type 1~14, of which MODY 2 and 3 might be the most common forms. Although MODY is currently classified as diabetes of a single gene defect, it has become clear that mutations in rare MODYs, such as MODY 5 and MODY 6, have small mutagenic effects and low penetrance. In addition, as there are differences in the clinical phenotypes caused by the same mutation even in the same family, other phenotypic modifying factors are thought to exist; MODY could well have characteristics of type 2 diabetes mellitus, which is of multifactorial origin. Here, we outline the effects of genetic and environmental factors on the known phenotypes of MODY, focusing mainly on the examples of MODY 5 and 6, which have low penetrance, as suggestive models for elucidating the multifactorial origin of type 2 diabetes mellitus.     

Role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indians.

AIMS: To determine the role of islet autoimmunity in the aetiology of different clinical subtypes of diabetes mellitus in young north Indian patients by measuring islet autoantibodies. METHODS: In a cross-sectional study, 145 young patients with diabetes (onset < 30 years) were subdivided into the following categories: Type 1 diabetes (n = 83), malnutrition-modulated diabetes mellitus (MMDM, n = 31) and fibro-calculous pancreatic diabetes (FCPD, n = 31). MMDM subjects presented with emaciation and severe insulin-requiring but ketosis-resistant diabetes, while FCPD was associated with idiopathic chronic calcific pancreatitis. Antibodies to glutamic acid decarboxylase (GADA) and IA-2 (IA-2 A) were detected by immunoprecipitation of 35S-labelled recombinant antigens and cytoplasmic islet cell antibody (ICA) by indirect immunofluorescence. RESULTS: GADA were present in a significant proportion (23%) of patients with MMDM. In contrast, IA-2 A was increased only among patients with Type 1 diabetes (22%), but not MMDM (3%, P < 0.05). Among patients with a duration of diabetes < 2 years, GADA and/or IA-2 A were found in 61% of Type 1 diabetic and 37% of MMDM patients (P < 0.01). MMDM patients who were positive for GADA had a shorter duration of diabetes, but did not differ in their age at onset of diabetes, body mass index, fasting plasma C-peptide, or frequency of thyroid microsomal and parietal cell antibodies. FCPD subjects had the lowest prevalence of autoantibodies: IA-2 and ICA were absent, while GADA were present in 7% (P < 0.05 vs. Type 1 diabetes). CONCLUSIONS: GADA, though not IA-2 A, were present in a substantial proportion of patients with the MMDM variant of diabetes, suggesting that islet autoimmunity may play a role in its pathogenesis. In contrast, none of the islet antibodies was increased in subjects with FCPD, making it likely that it is a secondary type of diabetes.     

Hepatitis C virus infection-related Type 1 diabetes mellitus.

BACKGROUND: Hepatitis C virus (HCV) has been associated with Type 2 diabetes mellitus, and many other viral infections have been associated with Type 1 diabetes mellitus (Type 1 DM). An association between HCV and Type 1 DM, however, has never been reported. We report the case of a 66-year-old man who developed Type 1 DM 1 year after a blood transfusion-related HCV infection. Testing of serum specimens obtained in the weeks following blood transfusion demonstrated evidence of both acute HCV infection and development of Type 1 DM-related autoantibodies. CASE REPORT: A 66-year-old Taiwanese male received blood transfusions during coronary artery bypass surgery in 1987. Serum specimens, obtained as part of a study on post-transfusion hepatitis, demonstrated that the patient had no evidence of hepatitis C prior to transfusion, but developed acute HCV infection after transfusion. One year later, the patient, who had no personal or family history of diabetes, presented with diabetic ketoacidosis, and tests for C-peptide confirmed that he had Type 1 DM. Testing of pre- and post-operative serum specimens demonstrated that the patient developed positive tests for islet cell and glutamic acid decarboxylase antibodies 4 weeks after transfusion, concurrent with the development of acute HCV infection. CONCLUSIONS: The simultaneous development of HCV infection and diabetes-related autoantibodies suggest a relationship between HCV and Type 1 DM.     

Childhood diabetes mellitus in Ethiopians

Of 1088 consecutive Ethiopian diabetic patients registered over 9 years 80 (7.4%) were diagnosed at or before age 15 years. There were 48 girls and 32 boys, with mean age of onset of 10.1 years. Diabetes had been present 10 years or less in 62, 11 to 20 years in 15, and more than 20 years in only 2. Twenty-two were rural, 27 had poverty certificates. Twenty-three have known diabetic relatives. The original mode of presentation could not be verified in 16, 7 presented in ketoacidosis, 5 were diagnosed by a diabetic relative, and the rest presented with the rapid onset of classical symptoms. To date, 43 have been ketoacidotic at least once. No pancreatic calcification was seen in 34 abdominal radiographs. Three of 6 newly diagnosed patients tested had islet cell surface antibodies. Three cases, initially suggestive of 'tropical malnutrition diabetes', evolved into typical type 1 diabetes. Serious complicating illnesses were tuberculosis (6), bacterial endocarditis (1) and rhinocerebral mucormycosis (1). Six patients have had metabolic cataracts. Ten patients (12%) have died, 4 of ketoacidosis and 4 of diabetic nephropathy. Childhood diabetes mellitus in Ethiopians is clinically very similar to type 1 diabetes elsewhere.     

Perinatal mortality in Type 2 diabetes mellitus.

AIMS: In many parts of the world the number of pregnancies in women with Type 2 diabetes mellitus (DM) now exceeds that in women with Type 1 DM, but there are few data published on perinatal mortality in Type 2 DM. This study reports observational data on perinatal mortality in Type 2 DM from a population with a high background rate of this disorder. METHODS: Over a 12-year period (1985-1997) at the Diabetes Clinic at National Women's Hospital, Auckland, there were 434 pregnancies in women with Type 2 DM (256 known and 178 diagnosed with gestational diabetes mellitus (GDM), but confirmed to have Type 2 DM early post-partum), 160 pregnancies in women with Type 1 DM and 932 in women with GDM. Perinatal mortality was classified as either intermediate fetal death (20-28 weeks' gestation), late fetal death (28 weeks' gestation to term) or early neonatal death (up to 1 month post-partum). RESULTS: The perinatal mortality in Type 2DM was 46.1/1,000, significantly higher than the rates for the general population (12.5), Type 1 DM (12.5) and GDM (8.9) (P < 0.0001). Congenital malformations accounted for only 10% of the perinatal mortality. There was a seven-fold increase in the rate of late fetal death and 2.5-fold increase in the rates of intermediate fetal and late neonatal death. Subjects with Type 2 DM were significantly older and more obese than subjects with Type 1 DM, and presented later to the diabetes service. CONCLUSIONS: Perinatal mortality in Type 2 DM is significantly increased, mainly owing to an excess of late fetal death. Maternal factors such as obesity may be important contributors to the high perinatal mortality. Women diagnosed with GDM who have unrecognized Type 2 DM are also at high risk, but perinatal mortality is low in women with milder degrees of glucose intolerance in pregnancy.     

糖尿病个体化医疗的研究进展

糖尿病领域的个体化医疗是在传统医学基础上结合基因组学、生物学标志检测等对糖尿病进行精确诊断和分层并指导治疗.基因检测可明确单基因突变糖尿病的病因如青少年起病的成人型糖尿病(MODY)、新生儿糖尿病(NDM)、线粒体基因突变糖尿病.应用生物学标志物如胰岛素抗体、C肽等可指导糖尿病精确分层并评估预后.而细胞色素P450 2C9 (CYP2C9)、有机阳离子转运蛋白(OCTs)、过氧化物酶体增殖物活化受体γ(PPARγ)相关基因变异对降糖药物的影响为患者选择降糖方案提供了参考.虽然个体化医疗在糖尿病领域还不能达到精确诊断及治疗,但未来将成为糖尿病领域的发展新趋势.