Does the use of insulin in a patient with liver dysfunction increase water retention in the body,i.e. cause insulin oedema?

A 68-year-old female with mild diabetes mellitus was admitted because of acute liver dysfunction due to autoimmune hepatitis. While 40 mg/day of prednisolone improved hepatic dysfunction dramatically, her diabetic milieu deteriorated seriously. The induced hyperglycaemia could not be controlled sufficiently, despite a high dose of insulin (> 110 units/day), suggesting the existence of insulin insensitivity and hyperinsulinaemia. Soon after introduction of insulin therapy, she developed severe anasarca, including marked peripheral oedema, ascites and pleural effusion. Anasarca eventually subsided within 4 weeks with the use of a diuretic agent. We conjectured that the side effects of insulin, such as anti-natriuresis and increased vascular permeability, might be pronounced in the presence of the hepatic dysfunction that accompanies insulin insensitivity, hyperinsulinaemia and hypoalbuminaemia.     

Six cases with severe insulin resistance (SIR) associated with mutations of insulin receptor: Is a Bartter-like syndrome a feature of congenital SIR?

Biallelic insulin receptor (INSR) gene mutations cause congenital syndromes of severe insulin resistance (SIR) known as Donohue syndrome (DS) and Rabson–Mendenhall syndrome (RMS). At presentation, DS and RMS are difficult to differentiate since they share many clinical features; however, while patients with DS usually die within 1 year of birth, individuals classified as RMS can reach adult age. INSR mutations can be also found in pubertal females with hyperinsulinism, hyperandrogenism, and acanthosis nigricans (type A SIR). We studied the INSR gene in five subjects with congenital SIR and in a patient with type A SIR. Nine biallelic INSR gene mutations (eight novels, including an in-frame deletion of INSR signal peptide) were identified in patients with congenital SIR; a heterozygous, spontaneous INSR mutation was detected in the patient with type A SIR. Two probands, presenting severe hirsutism at birth, died at the age of 3 months and were classified as DS, while other 2, currently 2 and 3 years old, were diagnosed with RMS (patients 3 and 4). The fifth patient with congenital SIR died when 14 months old. Nephrocalcinosis, hyperaldosteronism, hyperreninemia, and hypokalemia, in the absence of hypertension, were discovered in patients 3 and 5 when 24 and 4 months old, respectively. Patient 3, now 3 years/3 months old, still shows hyperreninemic hyperaldosteronism requiring potassium supplementation. We conclude that renal abnormalities resembling antenatal Bartter’s syndrome type II, recently reported also by others, is a common observation in patients with congenital SIR.     

Ghrelin suppression in overweight children: a manifestation of insulin resistance?

Ghrelin levels increase before and decrease after meals, potentially playing a role in meal initiation and satiety in an inverse pattern to that of insulin. The role of ghrelin in childhood obesity, a state associated with hyperinsulinism and insulin resistance, is not fully understood. Therefore, the aims of the present study were to investigate the dynamics of ghrelin suppression after an oral glucose tolerance test (OGTT) in normal weight (NW) vs overweight (OW) children and the relationship of ghrelin suppression to insulin sensitivity. Thirty-seven NW (15 males and 22 females; 9.4 +/- 0.2 yr old) and 23 OW (13 males and 10 females; 9.4 +/- 0.3 yr old) prepubertal children underwent a 3-h OGTT with measurements of ghrelin, glucose, and insulin. The fasting glucose to insulin ratio and the whole body insulin sensitivity index were used to assess the relationship of insulin sensitivity to fasting ghrelin and ghrelin response to the OGTT, respectively. Fasting ghrelin levels were significantly lower in OW vs NW youth and were mainly influenced by insulin sensitivity independent of adiposity. OGTT-induced absolute suppression in ghrelin was approximately 50% less in OW vs NW children, resulting in a similar percent suppression from baseline in the two groups despite a significantly higher insulin response in OW. The suppression of ghrelin correlated positively with the whole body insulin sensitivity index (r = 0.43; P = 0.001) and negatively with the change in insulin at 30 min (r = -0.31; P = 0.02). Fasting ghrelin, the change in insulin, and the change in glucose during the OGTT were the significant independent variables contributing to the variance in absolute suppression of ghrelin (r2 = 0.42; P < 0.001). Only the change in glucose contributed significantly to the variance in the percent suppression of ghrelin (r2 = 0.14; P = 0.019). Fasting ghrelin and ghrelin suppression after OGTT are modulated by insulin sensitivity. Alterations in ghrelin suppression in OW children may be yet another manifestation of the insulin resistance of obesity. Whether this is responsible for differences in satiety in OW individuals merits additional investigation.     

Loss of beta-cell mass leads to a reduction of pulse mass with normal periodicity,regularity and entrainment of pulsatile insulin secretion in Göttingen minipigs

Aims/hypothesis Type 2 diabetes is associated with impaired insulin action and secretion, including disturbed pulsatile release. Impaired pulsatility has been related to impaired insulin action, thus providing a possible link between release and action of insulin. Furthermore, progressive loss of beta-cell mass has been implicated in the pathogenesis of Type 2 diabetes. The aim of this study was to evaluate a possible link between loss of beta-cell mass and impaired pulsatile insulin secretion with special focus on glucose responsiveness of insulin secretion.Methods The kinetic and dynamic profiles of insulin in Göttingen minipigs are favourable for studies on pulsatility and a model of diabetes with reduced beta-cell mass has recently been established. Pigs were studied before (n=14) and after (n=10) reduction of beta-cell mass by nicotinamide (67 mg/kg) and streptozotocin (125 mg/kg) from 17.7±4.7 (normal animals,n=5) to 6.1±2.0 mg/kg. Pulsatile insulin secretion was examined during basal (n=8 normal, n=6 beta-cell reduced) and glucose entrained (n=6 normal, n=4 beta-cell reduced) conditions. Insulin concentration time series were analysed by autocorrelation and spectral analyses for periodicities and regularity, and by deconvolution for pulse frequency, mass and amplitude.Results Reduction of beta-cell mass and secondary hyperglycaemia resulted in correspondingly (r=0.7421, p=0.0275) reduced pulse mass (42% of normal during basal and 31% during entrained conditions) with normal periodicity (6.6±2.2 vs 5.8±2.4 min, p=0.50), regularity and entrainability of insulin secretion.Conclusion/interpretation Neither beta-cell loss, nor 2 weeks of slight hyperglycaemia, as seen in the beta-cell-reduced minipig, probably accounts for the disturbed insulin pulsatility observed in human Type 2 diabetes.Abbreviations ApEn Approximate entropy - NIA nicotinamide - LADA late onset autoimmune diabetes of the adult - STZ streptozotocin An erratum to this article can be found at     

Does abnormal insulin action or insulin secretion explain the increase in prevalence of impaired glucose metabolism with age in populations of different ethnicities?

Background

Age is associated with both impaired glucose and insulin metabolism. To what extent the age‐related changes in insulin resistance (IR) and β‐cell function contribute to the increase in prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) is less known, and this is investigated in this study.

Methods

This study included 6610 men and 7664 women of different ethnic groups aged 30‐69 years. IR and β‐cell function were examined by the homeostasis model assessment of insulin resistance (HOMA‐IR) and homeostasis model assessment of β‐cell function (HOMA‐B). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression analysis adjusting for body mass index and study.

Results

In Chinese men, the ORs (95% CIs) for IFG were 2.69 (1.70, 4.26), 2.51 (1.49, 4.21) and 2.89 (1.68, 4.97), respectively, in age groups of 40–49, 50–59 and 60–69 years compared with 30–39 years (p < 0.001 for trend); the corresponding figures for IGT were 1.73 (1.25, 2.38), 2.54 (1.78, 3.63) and 3.57 (2.46, 5.19) (p < 0.001 for trend). Similar trends for IGT were observed also in Chinese women and other ethnic groups, but not for IFG in Mauritius Indian and Creole men. Adjustment for HOMA‐IR and HOMA‐B reduced the ORs in all age groups of all ethnicities for both IFG and IGT, but the risk gradient between age groups remained particularly for the IGT.

Conclusions

The age‐related increase in glucose intolerance may not be fully explained by the defect in HOMA‐IR and HOMA‐B. As HOMA‐IR and HOMA‐B are only surrogate measures of insulin sensitivity and insulin secretion, the results need to be further investigated. Copyright © 2010 John Wiley & Sons, Ltd.     

Long-term outcome of insulin pump therapy in children with type 1 diabetes assessed in a large population-based case–control study

Aims/hypothesis

We determined the impact of insulin pump therapy on long-term glycaemic control, BMI, rate of severe hypoglycaemia and diabetic ketoacidosis (DKA) in children.

Methods

Patients on pump therapy at a single paediatric tertiary hospital were matched to patients treated by injections on the basis of age, duration of diabetes and HbA_1c at the time of pump start. HbA_1c, anthropometric data, episodes of severe hypoglycaemia and rates of hospitalisation for DKA were collected prospectively.

Results

A total of 345 patients on pump therapy were matched to controls on injections. The mean age, duration of diabetes at pump start and length of follow-up were 11.4 (±?3.5), 4.1 (±?3.0) and 3.5 (±?2.5) years, respectively. The mean HbA_1c reduction in the pump cohort was 0.6% (6.6 mmol/mol). This improved HbA_1c remained significant throughout the 7 years of follow-up. Pump therapy reduced severe hypoglycaemia from 14.7 to 7.2 events per 100 patient-years (p?<?0.001). In contrast, severe hypoglycaemia increased in the non-pump cohort over the same period from 6.8 to 10.2 events per 100 patient-years. The rate of hospitalisation for DKA was lower in the pump cohort (2.3 vs 4.7 per 100 patient-years, p?=?0.003) over the 1,160 patient-years of follow-up.

Conclusions/interpretation

This is the longest and largest study of insulin pump use in children and demonstrates that pump therapy provides a sustained improvement in glycaemic control, and reductions of severe hypoglycaemia and hospitalisation for DKA compared with a matched cohort using injections.     

Association of proinsulin-like molecules with lipids and fibrinogen in non-diabetic subjects — evidence against a modulating role for insulin

Summary Elevated concentrations of proinsulin-like molecules, other than insulin, may be associated with abnormalities of cardiovascular risk factors, promoting atherogenesis and thrombosis. Using specific assays we examined the relationship of levels of insulin, intact proinsulin and des-31,32 proinsulin to blood pressure, lipids, fibrinogen, factor VII and albumin excretion rate in 270 europids with normal glucose tolerance. After correcting for age and body mass index, fasting and 2-h insulin concentrations were significantly associated with those of total and LDL-cholesterol (r=0.18–0.22), HDL-cholesterol (both r=–0.20) and triglycerides (r=0.21 and 0.18), but not with blood pressure. Concentrations of intact and des-31,32 proinsulin showed significant associations with those of total and LDL-cholesterol (r=0.20–0.23), HDL-cholesterol (r=–0.31 and –0.32) and triglycerides (r=0.22 and 0.26). Fasting insulin and intact proinsulin concentrations were significantly associated with fibrinogen (r=0.15 and 0.18). Concentrations of proinsulin-like molecules comprised less than 10% of all insulin-like molecules, and so were calculated not to influence previously described relationships between insulin concentrations and cardiovascular risk factors measured using non-specific assays. In multiple regression analyses des-31,32 proinsulin concentration was more strongly associated with those of HDL-cholesterol (negatively), LDL-cholesterol and triglycerides than fasting insulin concentrations, while intact proinsulin replaced insulin concentrations in their relationships with fibrinogen. Our results show correlations between dyslipidaemia and proinsulin-like molecules at concentrations at which biological, insulin-like, activity appears unlikely. We also show relationships between LDL-cholesterol and fibrinogen and the proinsulin-like molecules. These results suggest that a causal relationship mediated by hyperinsulinaemia and insulin resistance is unlikely.Abbreviations PAI-1 Plasminogen activator inhibitor-1 - PI proinsulin - CV coefficient of variation     

Higher dose requirements with insulin detemir in type 2 diabetes—Three cases and a review of the literature

We report on three type 2 diabetic patients whose daily basal insulin dose requirements were substantially reduced after switching from insulin detemir to insulin glargine. Meta-analysis of three randomised trials of basal insulin initiation confirmed this increased insulin detemir dose requirement in type 2 patients. Potential explanations are discussed.     

Comparison of effectiveness of premixed insulin with long-acting insulin in diabetes: evidence from real-world cohort studies—systematic review and meta-analyses

The purpose of this research is to perform a systematic review and meta-analysis to compare effectiveness of premixed insulin (PM) and long-acting insulin (LA) based on cohort studies. Embase, Pubmed, Web of Science, Clinical.gov, and Opengray were searched. We included all cohort studies comparing the effectiveness of PM with LA on intermediate- or long-term outcomes. The weighted mean difference (WMD) was recorded for intermediate outcomes, and the risk ratio (RR) estimates were combined and weighted to produce pooled RR for long-term outcomes. Subgroup analysis was conducted by different insulin type and population. Eight studies involving 95,415 patients were included, in which six studies were used for quantitative analysis. Follow-up duration ranged from 6 months to 5 years. The meta-analysis indicated a comparable effect of PM and LA on the mean reduction in hemoglobin A1c (HbA1c) (WMD?=???0.03% [95% CI ??0.12–0.07]). Less fasting plasma glucose (FPG) declines were noticed with PM than LA (0.11 mmol/L [95% CI 0.03–0.18]). There was not statistically significant difference for post-prandial glucose (WMD?=???0.61 mmol/L [95% CI [??1.49–0.27]). PM was associated with further weight gain of 0.67 kg [95% CI 0.60–0.74] and more insulin consumption (WMD?=?11.72 U/day [95% CI 8.02–15.43]. The rates of hypoglycemia events were low but varied considerably. There was no significant difference in the effectiveness of PM and LA in real-world setting on HbA1c reduction, although PM was related with less FPG reductions, slight weight gain, and more insulin consumptions. Future real-world studies should concern about balanced oral hypoglycemic agents regimens between insulin cohorts and other potential confounding factors and assess relevant complications and death rate.