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Aims: To evaluate basal and prandial insulin initiation and titration in people with type 2 diabetes mellitus (T2DM) in primary care and to explore the feasibility of retrospective-continuous glucose monitoring (r-CGM) in guiding insulin dosing. The new model of care features General Practitioners (GPs) and Practice Nurses (PNs) working in an expanded role, with Credentialed Diabetes Educator - Registered Nurse (CDE-RN) support. Methods: Insulin-naive T2DM patients (HbA1c >7.5% [>58. mmol/mol] despite maximal oral therapy) from 22 general practices in Victoria, Australia commenced insulin glargine, with glulisine added as required. Each was randomised to receive r-CGM or self-monitoring of blood glucose (SMBG). Glycaemic control (HbA1c) was benchmarked against specialist ambulatory patients referred for insulin initiation. Results: Ninety-two patients mean age (range) 59 (28-77) years; 40% female mean (SD) diabetes duration 10.5 (6.1) years participated. HbA1c decreased from (median (IQR)) 9.9 (8.8, 11.2)%; 85 (73, 99) mmol/mol to 7.3 (6.9, 7.8)%; 56 (52, 62) mmol/mol at 24 weeks (p

The health burden of type 2 diabetes mellitus (T2DM) is increasing worldwide, with a substantial portion of this burden being due to the development of cardiovascular (CV) disease. Multiple individual randomised clinical trials of intensive versus conventional glucose control, based on the use of traditional oral hypoglycaemic agents, have failed to convincingly show that intensive glucose control significantly reduces CV disease outcomes. In recent times, two new approaches to lowering glucose levels have become available. One targets the "incretin effect" which involves the modulation of peptide hormones that normally regulate glucose levels when nutrients are given orally. The other approach is based on inhibiting the sodium-glucose co-transporter 2 (SGLT-2) in the tubules of the kidney to promote glycosuria. Incretin-based therapies, especially glucagon-like peptide-1 receptor analogues, reduce glucose levels, with a low risk of hypoglycaemia, by increasing insulin secretion, inhibiting glucagon release and increasing satiety. Clinical and experimental studies have also shown favourable effects on CV disease risk factors such as dyslipidaemia, blood pressure, and improvements in endothelial function and cardiac contractility. Similarly, SGLT-2 inhibitors reduce glucose levels with a low risk for hypoglycaemia and have positive effects on multiple CV disease risk factors. Whether the beneficial effects of these new glucose lowering approaches on surrogate markers of CV disease risk translates to an improvement in CV events remains unknown. Several CV outcome trials are currently being performed to show that at a minimum, these novel glucose lowering agents are safe, but also have positive CV benefits.

In people with type 1 diabetes (T1D), nocturnal hypoglycaemia (NH) can be slept through and can cause seizures, arrhythmias and death. Hypoglycaemia avoidance can induce hyperglycaemia and ketosis. Patient behaviour impacts clinical outcomes and may be changed by education.To develop and utilise a survey to evaluate patient self-management of overnight glycaemia in adults with T1D.Adults with T1D attending two Australian tertiary referral diabetes clinics completed a survey about their diabetes self-management and glycaemic control, including responses to hypothetical pre-bed blood glucose (BG) levels (4-20 mmol/L). Statistical analyses included t-tests, Chi square tests and ANOVA with significance considered at P0.05.There were 205 participants (103 females), with a mean (SD) age of 41 (17) years, T1D duration of 20 (16) years, HbA1c of 7.8(1.4)%, (61.3(8.2) mmol/mol), 38% on insulin pump therapy (CSII) and 36% with impaired hypoglycaemia awareness (IHA). Mean (SD) number of BG tests/day was 5.4 (2.7). Patients set higher BG target levels at bedtime and overnight: 7.5(1.4) and 7.1(1.3) mmol/L, respectively, compared to daytime (6.9(1.0); P0.0001 and P = 0.002 respectively). Only 36% of participants reported treating nocturnal hypoglycaemia (NH) with the recommended refined, then complex, carbohydrate. Only 28% of patients made safe choices in all bedtime BG scenarios, with higher rates for CSII users, P = 0.0005. Further education was desired by 32% of respondents, with higher rates in those with (44%) versus without IHA (25%), P = 0.006.Many adults with T1D have suboptimal knowledge and behaviour regarding overnight BG self-management. A survey, piloted herein, may facilitate the identification of patients who could benefit from further education.

This qualitative study explored trial participants' experiences of four nights of in-home closed loop.Sixteen adults with type 1 diabetes, who completed a randomized crossover trial, were interviewed after four consecutive nights of closed-loop. Interviews were audio recorded, transcribed, and analyzed with a coding framework developed to identify the main themes.Participants had a mean age of 42 ± 10 years, nine were women; mean diabetes duration was 27 ± 7 years, and all were using insulin pumps. Overall, first impressions were positive. Participants found closed-loop easy to use and understand. Most experienced more stable overnight glucose levels, although for some these were similar to usual care or higher than they expected. Compared with their usual treatment, they noticed the proactive nature of the closed-loop, being able to predict trends and deliver micro amounts of insulin. Most reported technical glitches or inconveniences during one or more nights, such as transmission problems, problematic connectivity between devices, ongoing alarms despite addressing low glucose levels, and sensor inaccuracy. Remote monitoring by the trial team and their own hypoglycemic awareness contributed to feelings of trust and safety. Although rare, safety concerns were raised, related to feeling unsure whether the system would respond in time to falling glucose levels.This study provides relevant insights for implementation of closed-loop in the real world. For people with diabetes who are less familiar with technology, remote monitoring for the first few days may provide reassurance, strengthen their trust/skills, and make closed-loop an acceptable option for more people with type 1 diabetes.

We documented temporal changes in the use of lipid-lowering medications and achievement of cholesterol targets in an Australian diabetes clinic. The number of patients using lipid-lowering therapy for primary or secondary cardiovascular prevention increased from 6 to 69% between 1993-1995 and 2014-2016, which corresponded to a decrease in low-density lipoprotein cholesterol levels from 3.7 to 2.4 mmol/L (P0.01).

We re-assess the fasting plasma glucose (FPG) and 2-h post-load glucose (2HPG) in the diagnosis of both prediabetes and type 2 diabetes mellitus by developing a gold standard based on beta-cell function. The gold standard was developed in a cohort of 2,152 adult subjects without severe renal or liver dysfunction that also had a 2-h oral glucose tolerance test (OGTT) during the Third National Health and Nutrition Examination Survey. Beta-cell function was computed based on a composite of insulin secretion (determined based on the insulin and glucose responses to the OGTT) and the homeostasis model insulin resistance index. The X-tile program was used to generate the most appropriate categories of minor, moderate and severe impairment of beta-cell function based on the best discrimination of ln(insulin secretion). Subjects with a moderate or severe impairment in beta-cell function were used to define prediabetes and diabetes, respectively, and was the standard against which the FPG and 2HPG were evaluated. It is shown that the current definitions of diabetes by the FPG and 2HPG mirror those derived using impairment of beta-cell function as the gold standard. It is also shown that lowering the cutoff for the FPG does little to improve its use in the screening for prediabetes. A major finding is that the current 2HPG cutoff is inadequate and thus in need of revision to >6.7 mmol/L (>120 mg/dL) from 7.8 mmol/L (140 mg/dL) for the lower cutoff. The use of a model of beta-cell function and impairment of insulin secretion has thus put the utility of the FPG and 2HPG into perspective: We recommend that performing an OGTT be considered pivotal for accurate identification of subjects with impaired beta-cell function (and thus prediabetes) and a revision of the OGTT lower cutoff be considered based on the results of this study.

AIMS: Reduced glucose effectiveness is a predictor of future glucose tolerance in individuals with a family history of type 2 diabetes. We examined retrospectively at 10 years in normoglycemic relatives of diabetic subjects (RELs) the pathophysiological role of glucose effectiveness in the development of isolated impaired fasting glucose, glucose intolerance, and acute insulin release.METHODS: At 0 years, 19 RELs and 18 matched control subjects had glucose effectiveness (GE), insulin sensitivity, acute insulin release (AIR)IVGTT, and disposition index measured during an iv glucose tolerance test (IVGTT), using the minimal model analysis. At 0 and 10 years, oral glucose tolerance (OGTT) and AIROGTT were determined.RESULTS: At 0 years, fasting glucose (FG) and GE were raised in RELs, but insulin sensitivity and AIROGTT were reduced (P ≤ .05) compared with controls. At 10 years, RELs developed raised fasting and 2-hour OGTT glucose. FG10y correlated significantly with FG0y and body mass index0y and negatively with √GE and 2-hour OGTT glucose10y with FG0y and negatively with AIRIVGTT0y and AIROGTT0y. Log AIROGTT10y correlated with √GE, log AIRIVGTT0y and log AIROGTT0y. Multiple regression analyses demonstrated the following: REL FG10y was predicted by combined FG0y, √GE and body mass index0y (radj(2) = 56%; P ≤ .001) and 2-hour OGTT glucose10y weakly related by FG0y,and √GE (r(adj)(2) = 25%; P = .06). Log AIROGTT10y was predicted by AIRIVGTT0y and √GE (r(adj)(2) = 46%; P ≤ .004).CONCLUSION: In normoglycemic RELs, a relative reduction of glucose effectiveness is an important contributor over 10 years to the development of isolated impaired fasting glucose and reduced acute insulin secretion.

Background This study aimed to compare the metabolic and insulin secretory responses to dexamethasone with the metabolic responses observed at 10 years in normoglycaemic relatives of type 2 diabetic and healthy control subjects. Methods Twenty relatives and 20 matched control subjects were studied twice at 0 year (pre- and post-dexamethasone) and at 10 years, employing a 75-g oral glucose tolerance test (OGTT), with serial measurements of glucose and insulin, for determination of glucose tolerance and calculations of acute insulin release (ΔI30/ΔG30; insulinogenic index) and insulin sensitivity (SIHOMA). Results Following dexamethasone, the relatives group developed varying degrees of glucose intolerance, associated with reduced insulin sensitivity and insulinogenic index. By 10 years, fasting glucose and 2-h OGTT glucose were raised in the relatives group, especially in the relatives most metabolically affected by dexamethasone, including a reduced insulinogenic index. Multiple regression analysis of the data in relatives demonstrated that the 2-h OGTT glucose and fasting glucose values at 10 years depended on the 0-year post-dexamethasone 2-h OGTT glucose, post-dexamethasone fasting glucose and post-dexamethasone insulin sensitivity, r2adj = 56% (p

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥ 12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Subcutaneously infused insulin may interfere with the function of nearby glucose-sensing electrodes and vice versa. The prototype of the Combo-Set device (Medtronic) incorporates a subcutaneous insulin delivery catheter and continuous glucose monitoring (CGM) sensor assembled on the same platform and separated by 11 mm. We aim to evaluate Combo-Set's insulin delivery and glucose-sensing functions.Ten subjects with type 1 diabetes wore a Combo-Set and a Sof-Sensor inserted subcutaneously in contralateral abdominal areas connected to iPro recorders (Medtronic) for 53.25 ± 0.75 h (mean ± standard deviation). The Combo-Set delivered insulin diluent except during meal tests on days 1 and 3 when insulin lispro was delivered as a meal bolus and postmeal basal. Venous plasma samples were collected at the following time points from meal start: 0, 30, 60, 120, and 180 min for insulin measurements. The accuracy of the Combo-Set sensors was evaluated and compared with that of the Sof-Sensor, with each referenced against capillary glucose values (Contour Link Meter, Bayer).Accuracy of the Combo-Set sensor was comparable to that of the Sof-Sensor. Clarke error grid analysis showed that 97% of Combo-Set and 93% of Sof-Sensor values were in the A+B regions (p = .20, not significant). The Combo-Set showed the expected postbolus peak insulin time (67 ± 9 min, mean ± standard error). One "no delivery" alarm occurred during the 21 patient days of use.A device providing for simultaneous adjacent placement of an insulin infusion catheter and a CGM sensor is feasible and functions within acceptable limits. The low "no delivery" alarm rate was similar to that of other infusion sets.

Background: After a diagnosis of diabetes mellitus, people not only have to cope with the physical aspects and common complications that require daily self-management, they are also faced with ongoing psychosocial challenges. Subsequently they find themselves having to navigate the health system to engage multidisciplinary supports; the combination of these factors often resulting in reduced health-related quality of life. To maintain optimal diabetes control, interventions need to incorporate psychosocial supports and a skill base for disease management. Therefore, our aim was to evaluate an 'Optimal Health Program' that adopts a person-centred approach and engages collaborative therapy to educate and support the psychosocial health of people diagnosed with type I or II diabetes. Methods: This prospective randomised controlled trial will include 166 people diagnosed with diabetes: 83 in the intervention (Optimal Health Program) and 83 in the control (usual care) group. Participants with type diabetes mellitus will be recruited through hospital outpatient clinics and diabetes community organisations. Participants in the intervention group will receive nine (8 + 1 booster session) sequential sessions, based on a structured treatment manual emphasising educational and psychosocial support self-efficacy and skills building. The primary outcome measures will be generalised self-efficacy (GSE) and health-related quality of life (AQoL-6D and EQ-5D). Secondary measures will be anxiety and depression (HADS), social and workplace functioning (WSAS), diabetes-related quality of life (DQoL), diabetes-related distress (PAID), and type of coping strategies (Brief COPE). In addition, a health economic cost analysis and process evaluations will be performed to assess the economic cost and efficacy of the program's operations, implementation and service delivery. Discussion: We envisage that the Optimal Health Program's emphasis on self-efficacy and self-management will provide participants with the skills and knowledge to achieve increased empowerment and independence in aspects of health, which in turn, will help participants deal more effectively with the physical and psychosocial complexities of diabetes. Trial registration:ACTRN12614001085662. Registered on 10 October 2014.

Seventeen subjects with confirmed primary aldosteronism and stable serum potassium (K) levels ≥ 3.5 mmol l-1 underwent saline suppression testing. They were retrospectively evaluated for changes in serum K levels post test. We found that there was a significant decrease in serum K levels post saline suppression test (3.7 ± 0.05 vs 3.5 ± 0.08, P = 0.01). This effect of saline suppression testing on serum K levels is not well described. We conclude that a decrease in serum K is common post-saline suppression test, even in subjects who are normokalemic pretest. The factors which predispose to the decrease in serum K level post saline load remain unclear.

Background Undiagnosed glycometabolic dysfunction is prominent amongst nondiabetic cardiac surgical patients, whereas perioperative dysglycemia is associated with adverse outcomes. This study assessed whether the preoperative level of insulin resistance predicts the degree of perioperative dysglycemia in nondiabetic, normoglycemic cardiac surgical patients. Methods Twenty-two nondiabetic patients awaiting cardiac operations were assessed for metabolic parameters and whole-body insulin resistance (mean glucose infusion [GINF] rate) using the hyperinsulinemic-euglycemic clamp. Intraoperative and postoperative glucose levels and treatment requirements were analyzed. Linear regression analysis was used to find predictors of baseline, peak intraoperative, and mean postoperative fasting blood glucose (FBG). Results The mean GINF recorded in nondiabetic, normoglycemic patients was 3.5 ± 1.4 mg/kg/min. The mean peak intraoperative and mean postoperative FBG concentrations were 154.9 ± 34.2 mg/dL (range, 108.1 to 227.0 mg/dL) and 120.7 ± 16.2 mg/dL (range, 100.9 to 154.9 mg/dL), respectively. The GINF correlated inversely with mean peak intraoperative (r = −0.7, p = 0.02) and mean postoperative FBG ( r = −0.8, p = 0.01). The GINF did not correlate with preoperative FBG levels ( r = 0.3, p = 0.4). Preoperative FBG did not correlate with peak intraoperative ( r = 0.4, p = 0.5) or mean postoperative FBG ( r = 0.5, p = 0.3). Conclusions Nondiabetic, normoglycemic cardiac surgical patients are highly insulin resistant using the hyperinsulinemic-euglycemic clamp. Preoperative insulin resistance, not FBG, is significantly associated with the development of perioperative dysglycemia. Insulin resistance screening may be useful to identify insulin resistance preoperatively and predict the degree of perioperative dysglycemia in cardiac surgical patients but should be performed with a more appropriate and reproducible test.

Aim: To perform a review of studies to identify the prevalence of depression and anxiety in adults with Type 1 diabetes mellitus compared to adults without Type 1 diabetes mellitus. Methods: A computer search was conducted using the PubMed, EBSCOhost, PsychINFO, Cochrane, CINAHL and MEDLINE from 2009 onwards. The essential information extracted from the identified publications were: participant demographics; measurement tools; prevalence of depression; diabetes-specific and non-diabetes specific risk and protective factors for depression or anxiety in people with Type 1 DM; outcomes for Type 1 DM management and complications; and relevant qualitative data. Results: An extensive literature search identified twenty-one key articles which were reviewed to provide strong evidence further supporting the notion that there is increased prevalence of comorbid depression and anxiety in Type 1 DM. Based on the literature reviewed, approximately one in five people living with Type 1 DM suffer from comorbid clinical depression, and one in four experience anxiety. There was variation in the exact rates reported between articles, however, which may be reflective of differences in methods or samples.Conclusion: The pertinence of the evidence analyzed in this review is underpinned by findings from large international studies that have shown depression results in worse health outcomes for individuals compared to any other chronic disease, including diabetes. Further, the combination of depression and diabetes leads to even poorer outcomes than does the combination of diabetes and other chronic diseases.

Background Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. Methods In a cross-sectional study, bias (eGFR – mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR >60 ml/min/1.73 m2 and rate of decline in GFR (ΔmGFR) > 3.3 ml/min/1.73 m2 per year, ΔmGFR (based on initial and final values) was compared with ΔeGFR by the CKD-EPI and MDRD equations over a mean of 9 years. Results In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m2 (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m2 (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m2 (p 90 ml/min/1.73 m2 as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.

Aim. To identify life transitions likely to impact diabetes self-care among young adults with Type 1 diabetes and their coping strategies during transition events. Background. Relationships among psychosocial stress, adjustment, coping and metabolic control affect clinical outcomes and mental health. Life transitions represent major change and are associated with stress that temporarily affects individuals’ problem-solving, coping abilities and blood glucose levels. Design. A qualitative interpretive inquiry. Method. Semi-structured interviews were conducted with 20 young adults with Type 1 diabetes and a constant comparative analysis method. Data and analysis was managed using QSR© NVivo 7 software. Results. Participants identified two significant transition groups: life development associated with adolescence, going through the education system, entering new relationships, motherhood and the workforce and relocating. Diabetes-related transitions included being diagnosed, developing diabetes complications, commencing insulin pump treatment and going on diabetes camps. Participants managed transitions using ‘strategic thinking and planning’ with strategies of ‘self-negotiation to minimise risks’; ‘managing diabetes using previous experiences’; ‘connecting with others with diabetes’; ‘actively seeing information to ‘patch’ knowledge gaps’; and ‘putting diabetes into perspective’. Conclusions. Several strategies are used to manage diabetes during transitions. Thinking and planning strategically was integral to glycaemic control and managing transitions. The impact of transitions on diabetes needs to be explored in larger and longitudinal studies to identify concrete strategies that assist diabetes care during life transitions. Relevance to clinical practice. It is important for health professionals to understand the emotional, social and cognitive factors operating during transitions to assist young adults with Type 1 diabetes to achieve good health outcomes by prioritising goals and plan flexible, timely, individualised and collaborative treatment.

Objective: To determine if screening for undiagnosed type 2 diabetes mellitus (T2DM) and pre-diabetes is feasible in an Australian ED; to estimate the prevalence of T2DM and pre-diabetes in the Australian ED population. Methods: Prospective cross-sectional prevalence survey in the ED of St Vincent's Hospital, Melbourne, an adult, tertiary referral centre seeing approximately 40 000 patients annually. A convenience sample of adult patients was screened with finger-prick random blood glucose and glycosylated haemoglobin (HbA1c); those over 6.0 mmol/L and 6.0% were referred for oral glucose tolerance test (OGTT). Diagnoses of T2DM and pre-diabetes were made according to World Health Organization definitions. Those not attending for OGTT were contacted by phone, and interviewed about their reasons. Results: Seven hundred and twenty-five patients were recruited; 135 (18.6%; 95% confidence intervals [CI] 15.9–21.6%) had known T2DM, leaving 590 screened, of whom 210 screened positive. Of the 192 referred for OGTT, 147 (77%) did not attend despite several telephone reminders. Of the 45 (23%) completing OGTT, pre-diabetes was present in eight (17.8%; 95% CI 9.0–31.6%) and T2DM in six (13.3%; 95% CI 5.9–26.6%). Many people interviewed (18/86, 21%) did not attend for OGTT on the advice of their doctors. Conclusions: This inner city tertiary ED has a high prevalence of T2DM, diagnosed and undiagnosed, with as much as half our population possibly affected. Although ED screening might have a high yield, opportunistic screening is not feasible, with difficulties in staff engagement and patient follow up for diagnostic testing. Future studies might consider finger-prick fasting blood glucose through a patient's general practitioner for diagnosis.

This study aims to provide a qualitative insight into the experiences of people living with type 1 diabetes mellitus (T1DM) who use an insulin pump, and thus inform diabetes care practices including psychological support programmes. Patients attending a specialist T1DM outpatient clinic were invited to share their experience of living with an insulin pump. Participants took part in either a semi-structured interview or a focus group, which were audio-recorded and transcribed. The data were analysed using a framework approach based on the Optimal Health Wheel comprised of six domains including Physical, Social, Intellectual, Emotional, Occupational and Spiritual values. A total of 15 individuals participated in a semi-structured interview (n=7) or a focus group (n=8). Participants were aged between 20 and 60 years with a duration of pump use ranging from 7 weeks to 9.5 years; the majority were female (n=12). A total of 19 sub-themes were identified under the six Optimal Health Wheel domains. It was concluded that the Optimal Health Wheel is a useful framework for qualitative data analysis. Its application synthesised some new themes (emotional–physical interplay, self-esteem and personality, and sense of self), as well as building on previously described themes such as self-management and the pump's physical presence. These provide insight into the lives of people living with T1DM and an insulin pump. Copyright © 2018 John Wiley & Sons.

Background We investigated the concordance between glucose effectiveness (SG) and insulin sensitivity (SI), derived from the unmodified dynamic non-insulin-assisted intravenous glucose tolerance test (IVGTT) implemented by SGMM and SIMM; simulation analysis and modelling/conversational interaction (SAAM/CONSAM) versus the eu/hyperglycaemic basal insulinaemic and the euglycaemic hyperinsulinaemic clamp (SGCLAMP and SICLAMP). Methods Twenty-seven of 30 normoglycaemic subjects completed a (1) euglycaemic hyperinsulinaemic clamp, (2) 6-h eu/hyperglycaemic near-normoinsulinaemic pancreatic clamp with hyperglycaemia present over the final 2 h of the clamp (Day 2 study), (3) identical clamp to (2) but with euglycaemia maintained over the entire 6 h (Day 3 study) and (4) IVGTT. SGCLAMP was calculated in two ways based on data from study (2) alone (Day 2 SGCLAMP210–240′) or from data from study day (2) and (3) (Day 2–3 SGCLAMP330–360′). Results SGMM was unrelated to the magnitude of endogenous insulin release (AIR). The single-day (Day 2) and two-day (Day 2 and 3) SGCLAMP protocols correlated (r = 0.72, p = 0.003), but SGCLAMP210–240′ was significantly (p = 0.001) higher than SGCLAMP330–360′. Employing the Day 2 and 3 SGCLAMP protocol, the whole body SGCLAMP330–360′ was similar to SGMM (1.80 ± 0.82 versus 1.73 ± 0.58 dL/min) and correlated (r = 0.45, p < 0.02). SGCLAMP210–240′ did not correlate with SGMM (r = 0.24). SIMM and SICLAMP were similar (0.093 ± 0.060 versus 0.087 ± 0.029 dL/min per mU/L) and correlated (r = 0.76, p < 0.001). Conclusions The time-dependent increase in glucose disposal observed during a prolonged 6-h clamp significantly influences the estimation of SGCLAMP, and significant concordance coefficients are observed between SGMM, and SGCLAMP330–360′, and SIMM and SICLAMP. Copyright © 2010 John Wiley & Sons, Ltd.

Summary Background The unmodified frequently sampled intravenous glucose tolerance test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. Objective To measure insulin sensitivity (Si) and glucose effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. Subjects and methods FSIGTs were performed in five patients, before and approximately 3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. Results Si was lower in insulinoma patients before, compared with after surgery (3·37 ± 0·62 vs. 6·24 ± 1·09 SE [×10−4] min−1µU−1 ml, P

Background: Current electrochemical glucose sensors use a single electrode. Multiple electrodes (redundancy) may enhance sensor performance. We evaluated an electrochemical redundant sensor (ERS) incorporating two working electrodes (WE1 and WE2) onto a single subcutaneous insertion platform with a processing algorithm providing a single real-time continuous glucose measure. Methods: Twenty-three adults with type 1 diabetes each wore two ERSs concurrently for 168 hours. Post-insertion a frequent sampling test (FST) was performed with ERS benchmarked against a glucose meter (Bayer Contour Link). Day 4 and 7 FSTs were performed with a standard meal and venous blood collected for reference glucose measurements (YSI and meter). Between visits, ERS was worn with capillary blood glucose testing ≥8 times/day. Sensor glucose data were processed prospectively. Results: Mean absolute relative deviation (MARD) for ERS day 1-7 (3,297 paired points with glucose meter) was (mean [SD]) 10.1 [11.5]% versus 11.4 [11.9]% for WE1 and 12.0 [11.9]% for WE2; P < .0001. ERS Clarke A and A+B were 90.2% and 99.8%, respectively. ERS day 4 plus day 7 MARD (1,237 pairs with YSI) was 9.4 [9.5]% versus 9.6 [9.7]% for WE1 and 9.9 [9.7]% for WE2; P = ns. ERS day 1-7 precision absolute relative deviation (PARD) was 9.9 [3.6]% versus 11.5 [6.2]% for WE1 and 10.1 [4.4]% for WE2; P = ns. ERS sensor display time was 97.8 [6.0]% versus 91.0 [22.3]% for WE1 and 94.1 [14.3]% for WE2; P < .05. Conclusions: Electrochemical redundancy enhances glucose sensor accuracy and display time compared with each individual sensing element alone. ERS performance compares favorably with ‘best-in-class’ of non-redundant sensors.

A 60-year-old woman with resistant hypertension, poorly controlled type 2 diabetes, and chronic obstructive pulmonary disease requiring inhaled corticosteroids was referred for investigation of Cushing’s syndrome. She had a BMI of 31 kg/m2, abdominal obesity, and proximal muscle wasting. Investigations showed a normal aldosterone-to-renin ratio, plasma metanephrines, and renal artery Doppler ultrasound fi ndings, but increased 24 h urine free cortisol concentration (454 nmol/L [normal range

This study assesses the autonomic function of patients who have regained awareness of hypoglycaemia following islet cell or whole pancreas transplant.Five patients with type 1 diabetes and either islet cell (four patients) or whole pancreas (one patient) transplant were assessed. These patients were age-matched and gender-matched to five patients with type 1 diabetes without transplant and preserved hypoglycaemia awareness and five healthy control participants without diabetes. All participants underwent (i) a battery of five cardiovascular autonomic function tests, (ii) quantitative sudomotor axonal reflex testing, and (iii) sympathetic skin response testing.Total recorded hypoglycaemia episodes per month fell from 76 pre-transplant to 13 at 0- to 3-month post-transplant (83% reduction). The percentage of hypoglycaemia episodes that patients were unaware of decreased from 97 to 69% at 0-3 months (p 0.001, Fisher's exact test) and to 20% after 12 months (p 0.0001, Fisher's exact test). This amelioration was maintained at the time of testing (mean time: 4.1 years later, range: 2-6 years). Presence of significant autonomic neuropathy was seen in all five transplanted patients (at least 2/3 above modalities abnormal) but in only one of the patients with diabetes without transplantation.The long-term maintenance of hypoglycaemia awareness that returns after islet cell/pancreas transplantation in patients with diabetes is not prevented by significant autonomic neuropathy and is better accounted for by other factors such as reversal of hypoglycaemia-associated autonomic failure.

Background The pathophysiological mechanism of diabetes mellitus in the presence of the 3243 A-G tRNALEU(UR) mitochondrial DNA mutation is thought to result from deficient insulin secretion. However, few subjects with normal glucose tolerance have been studied to determine the sequence of events resulting in the development of diabetes mellitus. Aim To determine whether abnormalities of insulin sensitivity, insulin secretion or glucose effectiveness are present in non-diabetic subjects with the 3243 A-G tRNALEU(UUR) mitochondrial DNA mutation. Methods Twelve non-diabetic subjects with the mutation were compared with 12 controls, matched for age and anthropometric parameters, using both oral and intravenous glucose tolerance tests, the latter with Minimal Model analysis. Results Following an oral glucose load we found significantly higher blood glucose levels at 90 min and 120 min and significantly higher insulin levels at 120 min and 180 min in non-diabetic subjects with the mutation but no difference in the insulinogenic indices at 30 min and 180 min. From the intravenous glucose tolerance test there was no difference in overall glucose tolerance, insulin sensitivity, first- or second-phase insulin secretion, proinsulin secretion or glucose effectiveness. Insulin-independent glucose disposal was increased in subjects with lower insulin sensitivity and declined with increasing age in subjects with the mutation but not in controls. Conclusions While there appear to be subtle defects of glucose handling in non-diabetic subjects with the 3243 mutation, these could not be explained by differences in insulin sensitivity or secretion. Diabet. Med. 18, 381–387 (2001)

Background Dysglycemia (encompassing impaired glucose tolerance and diabetes mellitus) arising after renal transplantation is common and confers a significant cardiovascular mortality risk. Nonetheless, the pathophysiology of posttransplant dysglycemia is not well described. The aim of this study was to prospectively and comprehensively assess glucose handling in renal transplant recipients from before to 12 months after transplantation to determine the underpinning pathophysiology. Materials and Methods Intravenous and oral glucose tolerance testing was conducted before and at 3 and 12 months posttransplantation. An intravenous glucose tolerance test was also performed on day 7 posttransplantation. We followed up 16 transplant recipients for 3 months and 14 recipients for 12 months. Insulin secretion, resistance and a disposition index (DI (IV)), a measure of β cell responsiveness in the context of prevailing insulin resistance, were also determined. Results At 12 months, 50% of renal transplant recipients had dysglycemia. Dysglycemia was associated with a dramatic fall in DI (IV) and this loss in β cell function was evident as early as 3 months posttransplantation (23.5 pretransplant; 6.4 at 3 months and 12.2 at 12 months posttransplant). Differences in the β cell response to oral glucose challenge were evident pretransplant in those destined to develop dysglycemia posttransplant (2-hour blood glucose level 5.6 mmol/L versus 6.8 mmol/L; P < 0.01). Conclusions Dysglycemia after renal transplantation is common, and the loss of insulin secretion is a major contributor. Subclinical differences in glucose handling are evident pretransplant in those destined to develop dysglycemia potentially heralding a susceptible β cell which under the stressors associated with transplantation fails.

OBJECTIVES: To determine the utility of various autoantibodies in predicting progression to clinical diabetes in first-degree relatives of patients with type 1 diabetes mellitus. PARTICIPANTS: 3315 first-degree relatives of patients with type 1 diabetes (1161 parents, 1206 siblings and 948 offspring) recruited through diabetes clinics, private endocrinologists, Diabetes Australia and the Juvenile Diabetes Foundation. MAIN OUTCOME MEASURES: Prevalence of islet cell antibodies (ICA) levels > or = 20 JDFu, insulin autoantibodies (IAA) levels > 100 nU/mL, and antibodies to glutamic acid decarboxylase (GADAb) and tyrosine phosphatase IA2 (IA2Ab); change in beta cell function over time; and development of clinical diabetes. RESULTS: 2.6% of relatives had elevated ICA levels, 1.3% had elevated IAA levels and 0.3% had both. High ICA levels were significantly more frequent in siblings than in offspring or parents, and were more frequent in relatives younger than 20 years. GADAb were detected in 68% and IA2Ab in 57% of relatives with elevated ICA and/or IAA levels. Diabetes developed in 33 relatives (25 siblings, 2 offspring and 6 parents). Before diagnosis of clinical diabetes, high ICA levels were detected in 18 (58%), high IAA levels in 7 (23%), both in 5 (15%), and either in 19 (61%); GADAb were detected in 26 (84%), IA2Ab in 13 (42%), both in 11 (35%), and either in 28 (90%). First phase insulin release (FPIR) less than 50 mU/L was very strongly associated with progression to diabetes. In relatives with FPIR initially greater than 50 mU/L who eventually developed diabetes, there was a gradual and continuous reduction in FPIR over time before diagnosis. CONCLUSIONS: Type 1 diabetes can be diagnosed in the preclinical stage. The recently described antibodies to glutamic acid decarboxylase and tyrosine phosphatase IA2 appear superior to ICA as screening tools for the preclinical diagnosis of type 1 diabetes.

Numerous factors impinge on β-cell function, and include the genetic background and insulin sensitivity of the individual. The aim of the present study was to evaluate the impact of a family history of non—insulin-dependent diabetes mellitus (NIDDM) on β-cell function and to determine whether the relationships between β-cell function and insulin sensitivity and age are influenced by a family history of diabetes. Thirty-three healthy control subjects (CON), 20 normal glucose-tolerant first-degree relatives of known NIDDM patients (REL), and 12 nondiabetic identical twins with an identical twin with known NIDDM were studied. Insulin and C-peptide responses to an acute intravenous glucose (AIRg) and glucagon bolus (at euglycemia [AIR [G.GON] ]) were measured, as well as each individual's insulin sensitivity. Fasting insulin and C-peptide levels were similar in all groups. AIRg was significantly reduced by 65% in the nondiabetic twins compared with the CON and REL groups, with the latter group being similar to CON, whereas for the AIR [G.GON] , the insulin responses in the twin subjects were reduced only by 35% compared with CON. Following stepwise (default) multiple regression analysis, three independent variables (insulin sensitivity, 23%; family history of NIDDM, 20%; and fasting glucose, 7%) were identified, and these combined to fit a model for prediction of acute β-cell responses to glucose that yielded an R 2 (adjusted) value of 50%. Following analysis of covariance (ANCOVA), a positive family history of NIDDM and insulin sensitivity but not the age of the subject were confirmed as separate factors affecting AIRg. In conclusion, in subjects with normal or mild glucose intolerance, the individual's genetic background and insulin sensitivity are important determinants of insulin secretion.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) affects up to 30% of the population and signifies increased risk of liver fibrosis and cirrhosis, type 2 diabetes, and cardiovascular disease. Therapies are limited. Weight loss is of benefit but is difficult to maintain. We aimed at examining the effect of the Mediterranean diet (MD), a diet high in monounsaturated fatty acids, on steatosis and insulin sensitivity, using gold standard techniques. Methods: Twelve non-diabetic subjects (6 Females/6 Males) with biopsy-proven NAFLD were recruited for a randomised, crossover 6-week dietary intervention study. All subjects undertook both the MD and a control diet, a low fat-high carbohydrate diet (LF/HCD), in random order with a 6-week wash-out period in- between. Insulin sensitivity was determined with a 3-h hyperinsulinemic–euglycemic clamp study and hepatic steatosis was assessed with localized magnetic resonance 1 H spectroscopy ( 1 H-MRS). Results: At baseline, subjects were abdominally obese with elevated fasting concentrations of glucose, insulin, triglycerides, ALT, and GGT. Insulin sensitivity at baseline was low (M = 2.7 ± 1.0 mg/kg/min � 1 ). Mean weight loss was not different between the two diets (p = 0.22). There was a significant relative reduction in hepatic steatosis after the MD compared with the LF/ HCD: 39 ± 4% versus 7 ± 3%, as measured by 1 H-MRS (p = 0.012). Insulin sensitivity improved with the MD, whereas after the LF/ HCD there was no change (p = 0.03 between diets). Conclusions: Even without weight loss, MD reduces liver steatosis and improves insulin sensitivity in an insulin-resistant population with NAFLD, compared to current dietary advice. This diet should be further investigated in subjects with NAFLD. 2013 European Association for the Study of the Liver. Published

Adults receiving conventional replacement therapy for hypopituitarism are known to have increased cardiovascular mortality. The aim of this study was to assess the lipid profiles of 30 hypopituitary adults compared with 2 case control groups, 1 matched for age, sex, and body mass index (BMI) and the second matched for age and sex only with a BMI representative of the general population. Fasting lipids, lipoproteins, and apoproteins (Apo) were determined by routine methods. Low density lipoprotein (LDL) particle size was determined by nondenaturing gradient gel electrophoresis. LDL size was significantly smaller in the hypopituitary group (25.9 +/- 0.1 nm) than in the BMI-matched (26.2 +/- 0.1 nm; P0.05) and standard control (26.3 +/- 0.1 nm; P0.01) groups. High density lipoprotein cholesterol levels in the hypopituitary group were significantly lower than those in the BMI-matched control group (1.13 +/- 0.06 vs. 1.34 +/- 0.06 mmol/L; P0.05) and the standard control group (1.38 +/- 0.06 mmol/L; P0.005). Apo A1 levels were also lower compared with those in the BMI-matched (122 +/- 6 vs. 137 +/- 4 mg/dL; P0.05) and the standard (143 +/- 4 mg/dL; P0.005) control groups. There was a trend toward higher triglyceride levels when the hypopituitary subjects were compared with the standard control group [1.4 (95% CI, 1.3-2.2) vs. 1.0 (95% CI, 0.9-1.4) mmol/L; P = 0.06]. These differences were more marked in the female subjects studied. No significant differences were noted in total cholesterol, LDL cholesterol, or Apo B levels. We conclude that hypopituitary patients receiving conventional replacement therapy have an atherogenic lipid profile characterized by small dense LDL, decreased high density lipoprotein cholesterol, and increased triglyceride levels, which may contribute to the excess cardiovascular mortality in this group.

A study was conducted to determine the effects of alcohol swabbing on reagent strip blood glucose (BG) measurements using Reflolux and Glucometer GX meters and the Exac Tech Pen. Sixty subjects were randomly allocated to one of the three meters. Each had three separate fingerpricks after either swabbing with 70% isopropyl alcohol and testing immediately or after drying for two minutes; or after no preparation; (n=180). BG was also determined at alcohol concentrations of 0%, 1%, 5%, 10% and 20% on hypo (1.2 mmol/l), normo (4.0 mmol/l) and hyperglycaemic (>28 mmol/) blood in vitro (six strips/meter/concentration, n=270). Increasing concentrations of alcohol caused reduction of BG at all glycaemias using the two meters (p=

An assay of plasma 1,5-anhydroglucitol was evaluated. Assay CVs, effects of four plasma freeze-thaw cycles, glucose up to 80 mmol/L and triglycerides up to 20 mmol/L were acceptable. 1,5-anhydroglucitol levels were significantly lower in diabetic vs. non-diabetic subjects and correlated inversely with renal function, but not with HbA1c.

Paired frequently sampled intravenous glucose tolerance tests (FSIGT) were performed on five highly trained athletes within 2 hours of completing a 6-day ultramarathon run (E) and after 2 weeks of complete rest (R). Severe exercise increased free fatty acid (FFA) levels (E 1.2 +/- 0.16 v 0.42 +/- 0.07 mmol/L, P < .01) and norepinephrine levels (E 573 +/- 141 v 224 +/- 33 pg/mL, P < .01), with only moderate reductions in glucose tolerance (glucose disappearance [Kg] E 1.06 +/- 0.2 v R 1.7 +/- 0.3 min-1 x 10(2), P < .05). The minimal model analysis of FSIGT data using the method of Bergman et al (Endocr Rev 6:45-86, 1985) showed a reduced second-phase insulin secretion ([phi 2] E 5.2 +/- 1.3 v 13 +/- 2.2 microU/mL.min-2 per mg/dL, P < .05) and glucose disposition index ([SI x phi 2] E 33.8 +/- 10 v 73.9 +/- 11 mg-1.dL.min-3 x 10(4), P < .02). Insulin sensitivity (SI) and glucose-mediated glucose disposal (SG) were unchanged (SI E 6.9 +/- 1.0 v 6.0 +/- 0.6 min-1 per microU/mL x 10(4); SG E 1.8 +/- 0.6 v 1.4 +/- 0.3 min-1 x 10(2)). Reduced glucose tolerance after prolonged extreme physical exercise was accompanied by reduced phi 2 and not by alterations of SI or SG, despite the marked increase of FFA levels. Elevated norepinephrine levels, reflecting activation of the sympathetic noradrenergic system, was also associated with the reduction in Kg. The reduction in phi 2 would promote mobilization of FFA, the predominant metabolic substrate in these endurance events.

Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of elevated EPI and CORT levels on KG, SI and SG were studied in dogs with alloxan-induced diabetes. Conscious dogs received SAL, EPI 20 ng μ kg−1 · min−1 for 30 min (short EPI) or 72 h (long EPI), or CORT 200 μg · kg−1 · min−1 for 60 min (short CORT) or 72 h (long CORT) before assessment of glucose metabolism by rapid sampling for glucose and insulin levels after 300 mg/kg i.v. glucose and exogenous insulin infusion designed to simulate the normal secretory pattern. With EPI infusion, KQ fell acutely from 2.9 ± 0.4 to 2.0 ± 0.2%/min (SAL vs. short EPI, P < 0.05), but rose to 3.4 ± 0.4%/min during long EPI. Minimal-model analysis of the glucose response with the insulin data as input showed that S1 decreased acutely from 4.7 ± 1.8 to 2.5 ± 0.6 × 10−5 min−1/pM (SAL vs. short EPI, P < 0.05), but rose to 4.5 ± 2.5 × 10−1 min−1/pM during long EPI. The effects of EPI on SG paralleled the results for KG and S1, with acute decline from 3.9 ± 0.4 to 2.1 ± 0.4 × 10−2 min−1 (SAL vs. short EPI, P < 0.05) and recovery to 3.3 ± 0.3 × 10−2 min−1 during long EPI. During CORT infusion, Kg tended to fall (SAL 2.9 ± 0.4 vs. short CORT 2.5 ± 0.5 vs. long CORT 2.2 ± 0.5%/min). This decline was related to a fall of S1 (SAL 4.7 ±1.8 vs. short CORT 2.7 ± 1.8 vs. long CORT 1.2 ± 0.7 × 10−1 min−1/pM, P < 0.05 long CORT vs. SAL), whereas SG levels were similar for the three groups. These results indicate that, in the absence of any compensatory change of insulin secretion, adaptation to the metabolic effects of long-term hormone elevation occurs for EPI but not CORT, which has a sustained effect on S1. Therefore, CORT may be more important than EPI as a contributor to long-term stress-induced hyperglycemia in people with type I diabetes.

Glucose effectiveness (S(g)) is an important component in glucose tolerance. Values of S(g) using "open loop" glucose kinetic computer programs are usually higher compared to closed loop method (CLM) programs that incorporate insulin secretion modeling. We aimed to test whether these differences are caused by (1) inclusion of insulin secretion modeling or (2) the method of representing plasma insulin values in the first few minutes of the frequently sampled intravenous glucose tolerance test (FSIGT).FSIGTs without insulin supplementation were performed in six healthy volunteers, and the Bergman minimal model was fitted to the data using the simulation and modeling program SAAM.The CLM, which represents the insulin data in the first few minutes by a best-fit curve extrapolated to the y-axis, yielded a significantly lower S(g) than the approach similar to the computer program MINMOD, where the first few minutes of insulin data are represented by a line joining the basal to the peak values (1.55 +/- 0.28 vs. 1.97 +/- 0.27 [SE] x 10(-2)/min, P0.05). This second analysis was then repeated while forcing the program to represent the insulin data after the insulin peak in the same way as in the CLM, obtaining an almost identical result for S(g) (1.99 +/- 0.29). Insulin sensitivity was not significantly affected.The higher S(g) estimates are caused by the method of representing the first few minutes of insulin data rather than by the incorporation of insulin secretion modeling. It is, therefore, important to know how the early insulin data are represented when comparing results from different computer modeling programs.

Chapter 1: Introduction and overview of the book. Introduction. Aims of the book. Chapter 2: presentation, diagnosis and classification of diabetes. The key role of insulin. Diabetes mellitus. The main types of diabetes. Prevalence of diabetes. Type 1 diabetes in children and adolescents. Case discussions. Chapter 3: Health assessment, management targets and deciding on a management plan. Introduction. The aims of diabetes management. Monitoring the effectiveness of the management plan. Holistic health assessment. Laboratory assessments. Multidisciplinary team and shared care. Case discussions. Chapter 4: Nutritional management and physical activity. Nutritional needs of people with diabetes. Obesity. Low calorie diets and weight loss medicines. Incidence and consequences of malnutrition. Measuring the carbohydrate content of food. Increasing mobility and exercise. Case discussions. Chapter 5: Pharmacotherapeutic management. Introduction. Quality us of medicines. Oral hypoglycaemic agents. Combining OHAs and insulin. Insulin. Sliding scales and top up doses. Lipid lowering agents. Antihypertensive agents. Salicylates. Case discussions. Chapter 6 Short term complications. Introduction. The main shirt tem complications. Hypoglycaemia. Causes of hypoglycaemia. Hypoglycaemic unawareness. Hyperglycaemia. Causes of Hyperglycaemia. Treating hyperglycaemia. Hyperglycaemic emergencies. Diabetic ketoacidosis. Hyperosmolar states. Lactic acidosis. Case discussions. Chapter 7 Long term complications. Introduction. Long term complications. Cardiovascular disease. Cerebrovascular disease. Nephropathy. Retinopathy. Neuropathy. Peripheral neuropathy. Autonomic neuropathy. Dental. Musculoskeletal. Chapter 8 Psychological and quality of life. Introduction. Depression. Signs and symptoms of depression. Tools used to measure depression. Quality of life. Case discussions. Chapter 9 Diabetes education. Introduction. Education processes. Aims of diabetes education. Survival skills education. Empowerment. Case discussions. Chapter 10 Gestational diabetes. Introduction. Managing gestational diabetes. Commencing insulin. Case discussions. Chapter 11 complementary and alternative therapies . Introduction. Profile of Cam users. Reasons for using CAM. Herbal and nutritional therapies. Complementary and conventional medicine interactions. Case discussions

In order to evaluate simultaneously in thyrotoxic subjects the relative contributions of insulin secretion, insulin-sensitivity (SI) and glucose-mediated (SG) glucose disposal to overall glucose tolerance, seven non-obese patients with thyrotoxicosis were studied by the minimal model analysis of the frequently sampled intravenous glucose tolerance test, before and greater than 1 month after being rendered euthyroid, and compared with eight healthy control subjects. Basal glucose, C-peptide and glucagon levels were similar in all groups but, in the toxic and euthyroid states, basal insulin levels were significantly elevated compared to the control group (11.2 +/- 2.0 and 7.9 +/- 1.1 vs 5.1 +/- 0.6 microU/ml, mean +/- SE, P less than 0.02). FFA levels were raised in the thyrotoxic subjects prior to treatment (0.95 +/- 0.11 vs 0.68 +/- 0.08 and 0.54 +/- 0.08 mmol/l, P less than 0.02). Glucose tolerance (Kg) was reduced in the thyrotoxic subjects compared to the euthyroid state (1.16 +/- 0.12 vs 1.44 +/- 0.13 per min, P less than 0.025) and control group (1.44 +/- 1.0 per min, 0.05 less than P less than 0.1). First phase (phi 1) and second phase (phi 2) insulin release were both significantly elevated in the thyrotoxic and euthyroid states compared to the control group (phi 1 7.10 +/- 1.88 and 5.29 +/- 1.03 vs 1.72 +/- 0.17 microU/mg/min X 10(-2), P less than 0.01; phi 2 18.64 +/- 3.14 and 16.74 +/- 4.48 vs 9.23 +/- 0.74 microU/mg/min X 10(-2) respectively, P less than 0.02). SG was similar in all groups but SI was significantly reduced in the thyrotoxic subjects compared to the control group (2.24 +/- 0.62 vs 5.92 +/- 1.50/min/microU/ml X 10(4), P less than 0.02) and rose post-treatment in the euthyroid subjects (4.23 +/- 1.75/min/microU/ml X 10(4)). In the thyrotoxic subjects before and after treatment, log SI correlated negatively with basal FFA levels (r = -0.57, P less than 0.05) and with phi 2 (r = -0.58, P less than 0.05). The fractional clearance rate of insulin was unaltered by the thyrotoxic state. It is concluded that in thyrotoxicosis the impairment of Kg is due to reduced insulin sensitivity in the presence of enhanced insulin secretion, but glucose-mediated glucose disposal is unaltered by the toxic state.

Prolonged moderate insulinaemia over 20 h in normal humans produces a significant reduction of in vivo insulin action. To examine the effects in man of such moderate hyperinsulinaemia on in vitro glucose metabolism, insulin-receptor binding, glucose transport and incorporation of glucose into lipid were determined in adipocytes isolated from paired gluteal fat biopsies, taken from six normal human volunteers before and 1 h after 20 h of exogenous hyperinsulinaemia (plasma insulin 38 +/- 3 mU/l). Specific binding of insulin to isolated adipocytes was not altered (6.7 +/- 0.7 versus 7.6 +/- 1.5% per 10(5) cells). Basal glucose transport of 3-O-[14C]methylglucose in the absence of insulin was reduced after hyperinsulinaemia (5.2 +/- 1.1 versus post 4.3 +/- 1.3 pmol/7 s per 10(5) cells, 0.1 less than P greater than 0.05; or expressed as percent of maximal response: 60 +/- 5 versus post 49 +/- 1%, P less than 0.05), but maximal transport (9.2 +/- 1.5 versus post 8.7 +/- 1.5 pmol/7 s per 10(5) cells) and ED50 (87 +/- 17 versus 67 +/- 15 pmol/l) were unchanged. Conversion of glucose into lipid, using 3-D-[3H]glucose, was unchanged basally, at maximal response or ED50 of the dose response curve. In conclusion, moderate 20 h in vivo hyperinsulinaemia in normal humans induces only a small change in basal vitro adipocyte glucose transport, and no change in insulin-receptor binding or in vitro incorporation of glucose into lipid. These data suggest that the adipocyte does not contribute to the impaired insulin action produced by in vivo moderate hyperinsulinaemia in man.

Prolonged near-physiological pulsatile insulin infusion has a greater hypoglycemie effect than continuous insulin infusion. We have previously shown that continuous hyperinsulinemia induces insulin insensitivity. This study examines the mechanisms responsible for the greater hypoglycemie effect of pulsatile insulin administration, in particular, whether prolonged pulsatile hyperinsulinemia induces insulin insensitivity. Basally and 1 h after cessation of a 20-h pulsatile infusion of insulin (0.5 mU · kg−1 · min−1), eight nondiabetic human subjects were assessed for 1) glucose turnover with [3-3H]glucose, 2) insulin sensitivity by minimal-model analysis of intravenous glucose tolerance tests, and 3) monocyte insulin-receptor binding. The time-averaged plasma insulin levels were 30 ± 5 mU/L (mean ± SE) during the infusion, which was similar to the levels achieved in our previous continuous hyperinsulinemia study. However, the average rate of glucose infusion to maintain euglycemia was 55% greater than in the previous study. Hepatic glucose production was -5.2 ±1.4 μmol · kg −1 · min−1 during the infusion but returned to preinfusion levels 1 h after the infusion was stopped. Insulin sensitivity (Si) and glucose tolerance (rate of glucose disappearance, Kg) showed changes opposite in direction to our previous continuous hyperinsulinemia study (pre- vs. postinfusion Kg 1.5 ± 0.1 vs. 1.7 ± 0.2 min−1 × 102, NS; pre- vs. postinfusion S, 8.4 ± 2.3 vs. 11.8 ± 3.7 min−1 · mU1 · L × 104 P < 0.05). There was no change in glucose-mediated glucose disposal (2.0 ± 0.2 vs. 2.3 ± 0.4 min−1 × 102) or pancreatic β-cell responsiveness (1st phase, 1.8 ± 0.2 vs. 2.2 ± 0.4 μU · ml−1 · min−1 · mg−1 · dl; 2nd phase, 9.9 ± 1.0 vs. 16.6 ± 3.5 μU · ml−1 · min∼−2 · mg−1 · dl). Monocyte insulin-receptor binding showed a postinfusion decrease. Plasma nonesterified fatty acids were profoundly suppressed during the infusion (0.05 ± 0.01 mM) and remained significantly (P < 0.05) suppressed 1 h postinfusion (0.21 ± 0.06 mM) compared with preinfusion (0.54 ± 0.08 mM). We conclude that despite a reduction in monocyte insulin-receptor binding, prolonged moderate pulsatile hyperinsulinemia, in contrast to equivalent continuous hyperinsulinemia, induced enhancement of insulin sensitivity, causing a greater hypoglycemie effect and greater suppression of plasma nonesterified-fatty acid levels.

Context Metformin therapy for adults and children with type 2 diabetes is well established. However, its role in the treatment of insulin resistance and obesity in children and adolescents is less clearly defined. Objective We assessed the effect of metformin on body composition and insulin sensitivity in pediatric subjects with exogenous obesity. Design and setting Patients referred to a pediatric endocrine clinic were enrolled in a randomized, double-blind, crossover trial. Patients Twenty-eight patients (13 males) aged 9-18 yr participated in the study. Intervention Patients received metformin (1 g twice daily) and placebo for 6 months, each with a 2-wk washout period. Main outcome measures Body composition (anthropometry, dual-energy x-ray absorptiometry, and abdominal magnetic resonance imaging), and insulin sensitivity (Si; minimal model, fasting insulin and glucose) were measured at baseline and 6 and 12 months. Results Mean age of subjects at baseline was 12.5 +/- 2.2 yr, median body mass index z-score 2.54 (range, 1.93-2.85). Metformin had a greater treatment effect over placebo for weight (-4.35 kg, P = 0.02), body mass index (-1.26 kg/m(2), P = 0.002), waist circumference (-2.8 cm, P = 0.003), sc abdominal adipose tissue (-52.5 cm(2), P = 0.002), and fasting insulin (-2.2 mU/liter, P = 0.011). Si improved in 45% of subjects while on metformin and 27% of subjects while on placebo (P = 0.21). Conclusions Metformin therapy for obese insulin-resistant pediatric patients results in significant improvement in body composition and fasting insulin. Although improvement in Si was noted in many individuals, Si was a less useful parameter for analysis of group data, possibly because of effects of variable compliance and changing Si during puberty.

The minimal model of Bergman et al has been used to yield estimates of insulin sensitivity (Si) and glucose effectiveness (Sg) in type 2 diabetes by incorporating exogenous insulin protocols into the regular intravenous glucose tolerance test (IVGTT). These estimates, however, are influenced by the degree to which the dose of exogenous insulin is greater than the physiologic response to a glucose load. Moreover, most studies have related to type 2 diabetes subjects whose diabetes was relatively mild in terms of therapeutic requirements. To develop a "minimal disturbance" approach in estimating Si and Sg in type 2 diabetes, we have used a reduced glucose load (200 mg/kg) and a "physiologic" insulin infusion throughout the IVGTT in a series of 8 patients, 5 of whom were insulin-requiring. Data from this approach were analyzed using the modelling program CONSAM to apply the Bergman model, either unmodified (BMM), or incorporating an additional delay element between the plasma and "remote" insulin compartments (MMD). Application of the MMD and extension of the IVGTT from 3 to 5 hours improved successful resolution of Si and Sg from 37.5% (BMM, 3-hour IVGTT) to 100% (MMD, 5-hour IVGTT). Si was reduced in these type 2 diabetes patients compared with normal subjects (1.86 +/- 0.60 v. 8.65 +/- 2.27 min(-1) x microU(-1) x mL x 10(4) P.01). The results were validated in the type 2 diabetes group using a 2-stage euglycemic clamp ((Si)CLAMP = 2.02 +/- 0.42 min(-1) x microU(-1) x mL x 10(4) P.4). Sg was not significantly reduced (2.00 +/- 0.25 type 2 diabetes v. 1.55 +/- 0.26 normal min(-1) x 10(2)). Data from a group of normal nondiabetic subjects was then analyzed using the MMD, but this approach did not enhance the fit of the model compared with the BMM. This result indicates that the delay in insulin action in type 2 diabetes represents an abnormality whereby the onset of insulin action cannot be described as a single phase in the transfer of insulin from plasma to the remote compartment. It is postulated that the physiologic basis for this delayed action may relate to transcapillary endothelial transfer of insulin, this process limiting the rate of onset of insulin action.

This study aimed to document patients' reasons for attendance at a “drop-in” centre serving a general diabetic clinic (n = 756). Over six months the following data were documented: reasons for attendance (self-initiated or referred and source or referrals); length of consultation; age and sex of clients; whether NIDDM or IDDM; and treatment modes. All 133 minor consultations ( 30 min) comprising 59 NIDDM (of whom 47 were insulin-treated) and 12 IDDM, 48 were self-initiated. The main reasons for major consultations were: 20 presented with persisting hyperglycaemia > 17 mmol/l (17 required insulin adjustment); eight had unfavourable social circumstances affecting diabetes management and required counselling; 10 requested ongoing diabetes education; six presented with foot lesions (two with neuropathic ulcers); and 10 diabetics came with non-diabetes-related health problems. Unexpectedly, there were no requests for dietary advice, and few for hypoglycaemia. There were six contacts by relatives, five parents of people with IDDM expressing concern about their child's lifestyle which compromised metabolic control and one husband of a person with NIDDM. We conclude that our clients demonstrate a definite need for diabetes-related education or advice between clinic visits. In our study the major reasons for seeking advice were for hyperglycaemia needing treatment modification, counselling and to increase diabetes knowledge.