Frits Holleman

Glucose variability; does it matter?

Overall lowering of glucose is of pivotal importance in the treatment of diabetes, with proven beneficial effects on microvascular and macrovascular outcomes. Still, patients with similar glycosylated hemoglobin levels and mean glucose values can have markedly different daily glucose excursions. The role of this glucose variability in pathophysiological pathways is the subject of debate. It is strongly related to oxidative stress in in vitro, animal, and human studies in an experimental setting. However, in real-life human studies including type 1 and type 2 diabetes patients, there is neither a reproducible relation with oxidative stress nor a correlation between short-term glucose variability and retinopathy, nephropathy, or neuropathy. On the other hand, there is some evidence that long-term glycemic variability might be related to microvascular complications in type 1 and type 2 diabetes. Regarding mortality, a convincing relationship with short-term glucose variability has only been demonstrated in nondiabetic, critically ill patients. Also, glucose variability may have a role in the prediction of severe hypoglycemia. In this review, we first provide an overview of the various methods to measure glucose variability. Second, we review current literature regarding glucose variability and its relation to oxidative stress, long-term diabetic complications, and hypoglycemia. Finally, we make recommendations on whether and how to target glucose variability, concluding that at present we lack both the compelling evidence and the means to target glucose variability separately from all efforts to lower mean glucose while avoiding hypoglycemia.

The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus.

Obesity and type 2 diabetes mellitus (T2DM) are attributed to a combination of genetic susceptibility and lifestyle factors. Their increasing prevalence necessitates further studies on modifiable causative factors and novel treatment options. The gut microbiota has emerged as an important contributor to the obesity—and T2DM—epidemic proposed to act by increasing energy harvest from the diet. Although obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota, the pathophysiological processes remain only partly understood. In this review we will describe the development of the adult human microbiome and discuss how the composition of the gut microbiota changes in response to modulating factors. The influence of short‐chain fatty acids, bile acids, prebiotics, probiotics, antibiotics and microbial transplantation is discussed from studies using animal and human models. Ultimately, we aim to translate these findings into therapeutic pathways for obesity and T2DM in humans.

Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity

BACKGROUND & AIMS Obesity has been associated with changes in the composition and function of the intestinal microbiota. Modulation of the microbiota by antibiotics also alters bile acid and glucose metabolism in mice. Hence, we hypothesized that short term administration of oral antibiotics in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d. At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS Vancomycin reduced fecal microbial diversity with a decrease of gram-positive bacteria (mainly Firmicutes) and a compensatory increase in gram-negative bacteria (mainly Proteobacteria). Concomitantly, vancomycin decreased fecal secondary bile acids with a simultaneous postprandial increase in primary bile acids in plasma (p<0.05). Moreover, changes in fecal bile acid concentrations were predominantly associated with altered Firmicutes. Finally, administration of vancomycin decreased peripheral insulin sensitivity (p<0.05). Amoxicillin did not affect any of these parameters. CONCLUSIONS Oral administration of vancomycin significantly impacts host physiology by decreasing intestinal microbiota diversity, bile acid dehydroxylation and peripheral insulin sensitivity in subjects with metabolic syndrome. These data show that intestinal microbiota, particularly of the Firmicutes phylum contributes to bile acid and glucose metabolism in humans. This trial is registered at the Dutch Trial Register (NTR2566).

Prevalence of diabetes mellitus and the performance of a risk score among Hindustani Surinamese, African Surinamese and ethnic Dutch: a cross-sectional population-based study

BackgroundWhile the prevalence of type 2 diabetes mellitus (DM) is high, tailored risk scores for screening among South Asian and African origin populations are lacking. The aim of this study was, first, to compare the prevalence of (known and newly detected) DM among Hindustani Surinamese, African Surinamese and ethnic Dutch (Dutch). Second, to develop a new risk score for DM. Third, to evaluate the performance of the risk score and to compare it to criteria derived from current guidelines.MethodsWe conducted a cross-sectional population based study among 336 Hindustani Surinamese, 593 African Surinamese and 486 Dutch, aged 35–60 years, in Amsterdam. Logistic regressing analyses were used to derive a risk score based on non-invasively determined characteristics. The diagnostic accuracy was assessed by the area under the Receiver-Operator Characteristic curve (AUC).ResultsHindustani Surinamese had the highest prevalence of DM, followed by African Surinamese and Dutch: 16.7, 8.1, 4.2% (age 35–44) and 35.0, 19.0, 8.2% (age 45–60), respectively. The risk score included ethnicity, body mass index, waist circumference, resting heart rate, first-degree relative with DM, hypertension and history of cardiovascular disease. Selection based on age alone showed the lowest AUC: between 0.57–0.62. The AUC of our score (0.74–0.80) was higher than that of criteria from guidelines based solely on age and BMI and as high as criteria that required invasive specimen collection.ConclusionIn Hindustani Surinamese and African Surinamese populations, screening for DM should not be limited to those over 45 years, as is advocated in several guidelines. If selective screening is indicated, our ethnicity based risk score performs well as a screening test for DM among these groups, particularly compared to the criteria based on age and/or body mass index derived from current guidelines.

The incidence of mild and severe hypoglycaemia in patients with type 2 diabetes mellitus treated with sulfonylureas: a systematic review and meta-analysis.

Patients with type 2 diabetes mellitus using sulfonylurea derivatives or insulin may experience hypoglycaemia. However, recent data regarding the incidence of hypoglycaemia are scarce. We conducted a systematic review and meta‐analysis to determine the proportion of patients with type 2 diabetes mellitus that experience hypoglycaemia when treated with sulfonylurea or insulin.

Ethnic Differences in Weight Loss and Diabetes Remission After Bariatric Surgery A meta-analysis

OBJECTIVE It has been postulated that the effectiveness of bariatric surgery varies between ethnic groups. However, data regarding this topic are inconclusive, as most studies included few patients from minority groups. We conducted a meta-analysis to determine the difference in percentage of excess weight loss (%EWL) 1–2 years after bariatric surgery in people of African and Caucasian descent. We also studied differences in diabetes mellitus (DM) remission. RESEARCH DESIGN AND METHODS We performed a MEDLINE and EMBASE search for studies reporting %EWL and/or DM remission after bariatric surgery and including both African Americans and Caucasians. The 613 publications obtained were reviewed. We included 14 studies (1,087 African Americans and 2,714 Caucasians); all provided data on %EWL and 3 on DM remission. We extracted surgery type, %EWL, and DM remission 1–2 years after surgery. After analyzing %EWL for any surgery type, we performed subanalyses for malabsorptive and restrictive surgery. RESULTS The overall absolute mean %EWL difference between African Americans and Caucasians was −8.36% (95% CI −10.79 to −5.93) significantly in favor of Caucasians. Results were similar for malabsorptive (−8.39% [−11.38 to −5.40]) and restrictive (−8.46% [−12.95 to −3.97]) surgery. The remission of DM was somewhat more frequent in African American patients than in Caucasian patients (1.41 [0.56–3.52]). However, this was not statistically significant. CONCLUSIONS In %EWL terms, bariatric surgery is more effective in Caucasians than in African Americans, regardless of procedure type. Further studies are needed to investigate the exact mechanisms behind these disparities and to determine whether ethnic differences exist in the remission of comorbidities after bariatric surgery.

The effect of diabetes on mortality in critically ill patients: a systematic review and meta-analysis

IntroductionCritically ill patients with diabetes are at increased risk for the development of complications, but the impact of diabetes on mortality is unclear. We conducted a systematic review and meta-analysis to determine the effect of diabetes on mortality in critically ill patients, making a distinction between different ICU types.MethodsWe performed an electronic search of MEDLINE and Embase for studies published from May 2005 to May 2010 that reported the mortality of adult ICU patients. Two reviewers independently screened the resultant 3,220 publications for information regarding ICU, in-hospital or 30-day mortality of patients with or without diabetes. The number of deaths among patients with or without diabetes and/or mortality risk associated with diabetes was extracted. When only crude survival data were provided, odds ratios (ORs) and standard errors were calculated. Data were synthesized using inverse variance with ORs as the effect measure. A random effects model was used because of anticipated heterogeneity.ResultsWe included 141 studies comprising 12,489,574 patients, including 2,705,624 deaths (21.7%). Of these patients, at least 2,327,178 (18.6%) had diabetes. Overall, no association between the presence of diabetes and mortality risk was found. Analysis by ICU type revealed a significant disadvantage for patients with diabetes for all mortality definitions when admitted to the surgical ICU (ICU mortality: OR [95% confidence interval] 1.48 [1.04 to 2.11]; in-hospital mortality: 1.59 [1.28 to 1.97]; 30-day mortality: 1.62 [1.13 to 2.34]). In medical and mixed ICUs, no effect of diabetes on all outcomes was found. Sensitivity analysis showed that the disadvantage in the diabetic surgical population was attributable to cardiac surgery patients (1.77 [1.45 to 2.16], P < 0.00001) and not to general surgery patients (1.21 [0.96 to 1.53], P = 0.11).ConclusionsOur meta-analysis shows that diabetes is not associated with increased mortality risk in any ICU population except cardiac surgery patients.

The interpretation of glucose clamp studies of long-acting insulin analogues: from physiology to marketing and back.

Glucose clamp studies assessing the time–action profile of long-acting insulin analogues have reported conflicting results. In an attempt to reconcile the data, we organised an expert meeting of four leading European clamp groups, during which consensus was reached on some but not all points discussed. In this paper, which reflects our personal views only, we aim to provide guidance for readers and reviewers on the interpretation of this type of clamp study and to clarify its inherent limitations.Glucose clamp studies are either performed manually or using an automated procedure, but differences in clamp methodology hardly seem a satisfactory explanation for the conflicting results. (Un)conscious investigator-related bias, especially during manual studies, cannot be ruled out, despite attempts at blinding the study insulin during the clamp.The duration of action of study insulins is influenced by many factors, such as glucose and insulin levels prior to injection, endogenous insulin secretion, insulin dose, definitions used for onset and end of action, and insulin sensitivity (which is influenced by the necessity of fasting during the clamp). These factors limit the translation of clamp study results into daily practice.Because of the inherent limitations of the glucose clamp technique and the lack of reproducibility of the outcomes, its results should be regarded as no more than an indication of the clinical action profile of long-acting insulin preparations.

Combining 123I-Metaiodobenzylguanidine SPECT/CT and 18F-FDG PET/CT for the Assessment of Brown Adipose Tissue Activity in Humans During Cold Exposure

Brown adipose tissue (BAT) has become a focus of research in the hope of finding a new target to fight obesity. Metabolic BAT activity can be visualized with 18F-FDG PET/CT. Furthermore, the sympathetic innervation of BAT can be visualized with the radiolabeled norepinephrine analog 123I-metaiodobenzylguanidine (123I-MIBG). We aimed to determine whether 123I-MIBG SPECT/CT and 18F-FDG PET/CT identify the same anatomic regions as active BAT in adult humans. Furthermore, we investigated whether the magnitude of BAT activity measured by these techniques correlated. Finally, we tried to establish the optimal time interval between 123I-MIBG administration and subsequent SPECT/CT acquisition to visualize sympathetic stimulation of BAT. Methods: Ten lean (body mass index, 19–25 kg/m2), healthy Caucasian men (age, 18–32 y) underwent one 18F-FDG PET/CT and two 123I-MIBG-SPECT/CT scans within a 2-wk interval. On 2 separate occasions, the subjects were exposed to mild cold (17°C) for 2 h after an overnight fast. After 1 h of cold exposure, 18F-FDG (one occasion) or 123I-MIBG (other occasion) was administered. 18F-FDG PET/CT was performed at 1 h after 18F-FDG administration, and 123I-MIBG-SPECT/CT was performed at 4 and 24 h after 123I-MIBG injection. Results: 18F-FDG uptake in BAT was observed in 8 of 10 subjects, whereas 123I-MIBG uptake was observed in 7 of 10 subjects in both the SPECT/CT scans acquired at 4 h after 123I-MIBG administration and the SPECT/CT scans acquired at 24 h after 123I-MIBG administration. All subjects who showed 123I-MIBG uptake in BAT also showed 18F-FDG uptake in BAT. There was no statistically significant correlation between maximal standardized uptake value of 18F-FDG and semiquantitative uptake of 123I-MIBG at 4 h after administration. However, a positive correlation was found between the maximal standardized uptake value of 18F-FDG and semiquantitative uptake of 123I-MIBG at 24 h after administration (r = 0.64, P = 0.04). Conclusion: 123I-MIBG SPECT/CT, as a marker of sympathetic activity, and 18F-FDG PET/CT, as a marker of metabolic activity, identified the same anatomic regions as active BAT. Moreover, when 123I-MIBG SPECT/CT was performed at 24 h after 123I-MIBG administration, the magnitude of BAT activity measured with these techniques correlated strongly. This finding not only supports that BAT activity in humans is sympathetically influenced but also identifies 123I-MIBG SPECT/CT, when performed 24 h after 123I-MIBG injection, as a method to visualize and quantify sympathetic stimulation of BAT.

Fasting and Postprandial Activity of Brown Adipose Tissue in Healthy Men

The role of brown adipose tissue (BAT) in adult metabolism is poorly understood. This study aimed to examine the differential effects of an overnight fast and the postprandial state on BAT activity. Methods: We included 10 healthy, lean male volunteers. BAT uptake of glucose was visualized using 18F-FDG PET/CT during mild cold exposure. Each subject underwent PET/CT twice. The first scan was obtained after an overnight fast; the second after a standardized meal. Results: 18F-FDG uptake in BAT was observed in 6 of 10 volunteers. These subjects were found to have a higher maximal standardized uptake value when fasting (median, 13.1 g/mL; range, 6.1–27.6 g/mL) than when in the postprandial state (median, 6.8 g/mL; range, 2.1–13.4 g/mL) (P = 0.03). Conclusion: Cold-stimulated 18F-FDG uptake by BAT in humans is more pronounced during fasting. The lower maximal standardized uptake value in the postprandial state may be explained by increased insulin-stimulated glucose uptake in muscle.