The role of glucose-stimulated release of GLP-1 in the development of obesity and type 2 diabetes is unclear. We assessed GLP-1 response to oral glucose in a large study population of lean and obese ...men and women with normal and impaired glucose regulation. Circulating concentrations of glucose, insulin, and GLP-1 during an oral glucose tolerance test (OGTT) were analyzed in individuals with normal glucose tolerance (NGT) (n = 774), prediabetes (n = 525), or screen-detected type 2 diabetes (n = 163) who attended the Danish ADDITION-PRO study (n = 1,462). Compared with individuals with NGT, women with prediabetes or type 2 diabetes had 25% lower GLP-1 response to an OGTT, and both men and women with prediabetes or type 2 diabetes had 16-21% lower 120-min GLP-1 concentrations independent of age and obesity. Obese and overweight individuals had up to 20% reduced GLP-1 response to oral glucose compared with normal weight individuals independent of glucose tolerance status. Higher GLP-1 responses were associated with better insulin sensitivity and β-cell function, older age, and lesser degree of obesity. Our findings indicate that a reduction in GLP-1 response to oral glucose occurs prior to the development of type 2 diabetes and obesity, which can have consequences for early prevention strategies for diabetes.
Aims/hypothesis
The secretion of glucagon is controlled by blood glucose and inappropriate secretion of glucagon contributes to hyperglycaemia in diabetes. Besides its role in glucose regulation, ...glucagon regulates amino acid metabolism in hepatocytes by increasing ureagenesis. Disruption of this mechanism causes hyperaminoacidaemia, which in turn increases glucagon secretion. We hypothesised that hepatic insulin resistance (secondary to hepatic steatosis) via defective glucagon signalling/glucagon resistance would lead to impaired ureagenesis and, hence, increased plasma concentrations of glucagonotropic amino acids and, subsequently, glucagon.
Methods
To examine the association between glucagon and amino acids, and to explore whether this relationship was modified by hepatic insulin resistance, we studied a well-characterised cohort of 1408 individuals with normal and impaired glucose regulation. In this cohort, we have previously reported insulin resistance to be accompanied by increased plasma concentrations of glucagon. We now measure plasma levels of amino acids in the same cohort. HOMA-IR was calculated as a marker of hepatic insulin resistance.
Results
Fasting levels of glucagonotropic amino acids and glucagon were significantly and inversely associated in linear regression models (persisting after adjustment for age, sex and BMI). Increasing levels of hepatic, but not peripheral insulin resistance (
p
> 0.166) attenuated the association between glucagon and circulating levels of alanine, glutamine and tyrosine, and was significantly associated with hyperaminoacidaemia and hyperglucagonaemia. A doubling of the calculated glucagon–alanine index was significantly associated with a 30% increase in hepatic insulin resistance, a 7% increase in plasma alanine aminotransferase levels, and a 14% increase in plasma γ-glutamyltransferase levels.
Conclusions/interpretation
This cross-sectional study supports the existence of a liver–alpha cell axis in humans: glucagon regulates plasma levels of amino acids, which in turn feedback to regulate the secretion of glucagon. With hepatic insulin resistance, reflecting hepatic steatosis, the feedback cycle is disrupted, leading to hyperaminoacidaemia and hyperglucagonaemia. The glucagon–alanine index is suggested as a relevant marker for hepatic glucagon signalling.
Aims/hypothesis
We aimed to investigate the short-term efficacy and safety of three glucose-lowering interventions in overweight or obese individuals with prediabetes defined by HbA
1c
.
Methods
The ...PRE-D Trial was a randomised, controlled, parallel, multi-arm, open-label, non-blinded trial performed at Steno Diabetes Center Copenhagen, Gentofte, Denmark. One hundred and twenty participants with BMI ≥25 kg/m
2
, 30–70 years of age, and prediabetes (HbA
1c
39–47 mmol/mol 5.7–6.4%) were randomised 1:1:1:1 to dapagliflozin (10 mg once daily), metformin (1700 mg daily), interval-based exercise (5 days/week, 30 min/session) or control (habitual lifestyle). Participants were examined at baseline and at 6, 13 and 26 weeks after randomisation. The primary outcome was the 13 week change in glycaemic variability (calculated as mean amplitude of glycaemic excursions MAGE) determined using a continuous glucose monitoring system (pre-specified minimal clinically important difference in MAGE ∼30%).
Results
One hundred and twelve participants attended the examination at 13 weeks and 111 attended the follow-up visit at 26 weeks. Compared with the control group, there was a small decrease in MAGE in the dapagliflozin group (17.1% 95% CI 0.7, 30.8,
p
= 0.042) and a small, non-significant, reduction in the exercise group (15.3% 95% CI −1.2, 29.1,
p
= 0.067), whereas MAGE was unchanged in the metformin group (0.1% 95% CI −16.1, 19.4,
p
= 0.991)). Compared with the metformin group, MAGE was 17.2% (95% CI 0.8, 30.9;
p
= 0.041) lower in the dapagliflozin group and 15.4% (95% CI −1.1, 29.1;
p
= 0.065) lower in the exercise group after 13 weeks, with no difference between exercise and dapagliflozin (2.2% 95% CI −14.8, 22.5,
p
= 0.815). One serious adverse event occurred in the control group (lung cancer).
Conclusions/interpretation
Treatment with dapagliflozin and interval-based exercise lead to similar but small improvements in glycaemic variability compared with control and metformin therapy. The clinical importance of these findings in prediabetes is uncertain.
Trial registration
ClinicalTrials.gov
NCT02695810
Funding
The study was funded by the Novo Nordisk Foundation, AstraZeneca AB, the Danish Innovation Foundation, the University of Copenhagen and Ascensia Diabetes Care Denmark ApS
Graphical abstract
Autonomic nervous system dysfunction is associated with impaired glucose metabolism, but the temporality of this association remains unclear in individuals without diabetes. We investigated the ...association of autonomic function with 5-year changes in glucose metabolism in individuals without diabetes.
Analyses were based on 9,000 person-examinations for 3,631 participants without diabetes in the Whitehall II cohort. Measures of autonomic function included 5-min resting heart rate and six heart rate variability (HRV) indices. Associations between baseline autonomic function measures and 5-year changes in fasting and 2-h plasma glucose, serum insulin concentrations, insulin sensitivity (insulin sensitivity index ISI
and HOMA of insulin sensitivity), and β-cell function (HOMA of β-cell function) were estimated in models adjusting for age, sex, ethnicity, metabolic factors, and medication.
A 10-bpm higher resting heart rate was associated with 5-year changes in fasting and 2-h insulin and ISI
of 3.3% change (95% CI 1.8; 4.8),
< 0.001; 3.3% change (1.3; 5.3),
= 0.001; and -1.4% change (-2.4; -0.3),
= 0.009, respectively. In models adjusted for age, sex, and ethnicity, higher baseline values of several HRV indices were associated with a 5-year decrease in fasting and 2-h insulin and ISI
. However, significance was lost by full adjustment. A majority of HRV indices exhibited a trend toward higher values being associated with lower insulin levels and higher insulin sensitivity.
Higher resting heart rate in individuals without diabetes is associated with future unfavorable changes in insulin levels and insulin sensitivity. Associations may be mediated via autonomic function; however, results are inconclusive. Resting heart rate may be a risk marker for future pathophysiological changes in glucose metabolism.
Abstract
Context:
Recent studies have suggested that a subgroup of obese individuals is not at increased risk of obesity-related complications. This subgroup has been referred to as metabolically ...healthy obese.
Objective:
To investigate whether obesity is a risk factor for development of ischemic heart disease (IHD) irrespective of metabolic health.
Design:
In all, 6238 men and women from the Danish prospective Inter99 study were followed during 10.6 (standard deviation = 1.7) years.
Setting:
General community.
Participants:
Participants were classified according to body mass index and four metabolic risk factors (low high-density lipoprotein cholesterol, elevated blood pressure, triglycerides, and fasting plasma glucose). Metabolically healthy individuals were defined as having no metabolic risk factors, and metabolically unhealthy individuals were defined as having a minimum of one.
Main Outcome Measures:
IHD.
Results:
During follow-up, 323 participants developed IHD. Metabolically healthy obese men had increased risk of IHD compared with metabolically healthy normal-weight men hazard ratio (HR), 3.1; 95% confidence interval (CI), 1.1 to 8.2). The corresponding results for women were less pronounced (HR, 1.8; 95% CI, 0.7 to 4.8). Being metabolically healthy but overweight was not associated with higher risk of IHD in men (HR, 1.1; 95% CI, 0.5 to 2.4), and in women the risk was only slightly increased and insignificant (HR, 1.5; 95% CI, 0.8 to 3.0). A substantial proportion of metabolically healthy individuals became metabolically unhealthy after 5 years of follow-up. When these changes in exposure status were taken into account, slightly higher risk estimates were found.
Conclusions:
Being obese is associated with higher incidence of IHD irrespective of metabolic status, and we question the feasibility of denoting a subgroup of obese individuals as metabolically healthy.
We studied the risk of ischemic heart disease (IHD) in the Inter99 cohort and found that metabolically healthy obese men had increased risk of IHD compared with metabolically healthy normal-weight men.
Patients with type 2 diabetes vary greatly with respect to degree of obesity at time of diagnosis. To address the heterogeneity of type 2 diabetes, we characterised patterns of change in body mass ...index (BMI) and other cardiometabolic risk factors before type 2 diabetes diagnosis.
We studied 6,705 participants from the Whitehall II study, an observational prospective cohort study of civil servants based in London. White men and women, initially free of diabetes, were followed with 5-yearly clinical examinations from 1991-2009 for a median of 14.1 years (interquartile range IQR: 8.7-16.2 years). Type 2 diabetes developed in 645 (1,209 person-examinations) and 6,060 remained free of diabetes during follow-up (14,060 person-examinations). Latent class trajectory analysis of incident diabetes cases was used to identify patterns of pre-disease BMI. Associated trajectories of cardiometabolic risk factors were studied using adjusted mixed-effects models. Three patterns of BMI changes were identified. Most participants belonged to the "stable overweight" group (n = 604, 94%) with a relatively constant BMI level within the overweight category throughout follow-up. They experienced slightly worsening of beta cell function and insulin sensitivity from 5 years prior to diagnosis. A small group of "progressive weight gainers" (n = 15) exhibited a pattern of consistent weight gain before diagnosis. Linear increases in blood pressure and an exponential increase in insulin resistance a few years before diagnosis accompanied the weight gain. The "persistently obese" (n = 26) were severely obese throughout the whole 18 years before diabetes diagnosis. They experienced an initial beta cell compensation followed by loss of beta cell function, whereas insulin sensitivity was relatively stable. Since the generalizability of these findings is limited, the results need confirmation in other study populations.
Three patterns of obesity changes prior to diabetes diagnosis were accompanied by distinct trajectories of insulin resistance and other cardiometabolic risk factors in a white, British population. While these results should be verified independently, the great majority of patients had modest weight gain prior to diagnosis. These results suggest that strategies focusing on small weight reductions for the entire population may be more beneficial than predominantly focusing on weight loss for high-risk individuals.
Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before ...onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional.
We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers.
Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin.
Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.
Most clinicians acknowledge that type 2 diabetes is multifactorial and has heterogeneous characteristics, but neither prevention nor treatment is systematically stratified. To address the ...heterogeneity of the disease, we examined whether patients diagnosed on the basis of fasting glucose concentrations, those diagnosed on the basis of 2 h concentrations, and those diagnosed on the basis of both criteria differed in terms of pathogenesis or cardiovascular risks.
Retrospectively, we analysed trajectories of cardiometabolic risk factors and 10 year cardiovascular risks in the prospective Whitehall II study cohort by use of multilevel longitudinal modelling. Participants were diagnosed by 75 g oral glucose-tolerance tests. We classified those diagnosed with type 2 diabetes into three subgroups: diagnosed on the basis of fasting glucose concentrations, diagnosed on the basis of 2 h glucose concentrations, and diagnosed on the basis of both concentrations. We also developed a classification tree for identification of individuals who are likely to have high fasting and 2 h glucose concentrations, but for whom only fasting concentrations are available.
Median follow-up was 14·2 years with 15 826 person-examinations (1991–2009). Of 10 308 individuals, 6843 were included and 6569 remained diabetes free. 274 cases of type 2 diabetes were identified: 55 had high fasting glucose concentrations only, 148 had high 2 h concentrations only, and 71 had high fasting and 2 h concentrations. At diagnosis, participants with high fasting and 2 h glucose concentrations had higher mean body-mass indices (30·9 kg/m2 SD 5·7) than did those with high fasting concentrations (28·4 kg/m2 4·4; p=0·0009) or 2 h concentrations (27·9 kg/m2 4·9; <0·0001). Mean glycated haemoglobin A1c concentrations were also higher in the fasting and 2 h subgroup (7·4% 1·6) than in the fasting (5·9% 0·5; <0·0001) or 2 h (5·9% 0·6; <0·0001) sugroups. Additionally, the fasting and 2 h subgroup had a higher proportion of individuals with moderate or high risk of cardiovascular disease than did the fasting subgroup (p=0·02). A classic pattern of β-cell decompensation before diagnosis was noted only in the fasting and 2 h subgroup. Additionally, glucose concentrations and insulin resistance accelerated more substantially before diagnosis in the fasting and 2 h subgroup than in the fasting subgroup or the 2 h subgroup.
Patients with type 2 diabetes diagnosed on the basis of increased fasting glucose concentrations or 2 h glucose concentrations, or both, have distinct cardiometabolic risk development before diagnosis.
UK Medical Research Council, UK Economic and Social Research Council, British Heart Foundation, UK Health and Safety Executive, UK Department of Health, US National Heart Lung and Blood Institute, US National Institute on Aging, US Agency for Health Care Policy Research, and John D and Catherine T MacArthur Foundation.
Type 2 diabetes (T2D), a multifactorial disease influenced by host genetics and environmental factors, is the most common endocrine disease. Several studies have shown that the gut microbiota as a ...close-up environmental mediator influences host physiology including metabolism. The aim of the present study is to examine the compositional and functional potential of the gut microbiota across individuals from Denmark and South India with a focus on T2D. Many earlier studies have investigated the microbiome aspects of T2D, and it has also been anticipated that such microbial associations would be dependent on diet and ethnic origin. However, there has been no large scale trans-ethnic microbiome study earlier in this direction aimed at evaluating any "universal" microbiome signature of T2D.
16S ribosomal RNA gene amplicon sequencing was performed on stool samples from 279 Danish and 294 Indian study participants. Any differences between the gut microbiota of both populations were explored using diversity measures and negative binomial Wald tests. Study samples were stratified to discover global and country-specific microbial signatures for T2D and treatment with the anti-hyperglycemic drug, metformin. To identify taxonomical and functional signatures of the gut microbiota for T2D and metformin treatment, we used alpha and beta diversity measures and differential abundances analysis, comparing metformin-naive T2D patients, metformin-treated T2D patients, and normoglycemic individuals.
Overall, the gut microbial communities of Danes and Indians are compositionally very different. By analyzing the combined study materials, we identify microbial taxonomic and functional signatures for T2D and metformin treatment. T2D patients have an increased relative abundance of two operational taxonomic units (OTUs) from the Lachnospiraceae family, and a decreased abundance of Subdoligranulum and Butyricicoccus. Studying each population per se, we identified T2D-related microbial changes at the taxonomic level within the Danish population only. Alpha diversity indices show that there is no significant difference between normoglycemic individuals and metformin-naive T2D patients, whereas microbial richness is significantly decreased in metformin-treated T2D patients compared to metformin-naive T2D patients and normoglycemic individuals. Enrichment of two OTUs from Bacteroides and depletion of Faecalibacterium constitute a trans-ethnic signature of metformin treatment.
We demonstrate major compositional differences of the gut microbiota between Danish and South Indian individuals, some of which may relate to differences in ethnicity, lifestyle, and demography. By comparing metformin-naive T2D patients and normoglycemic individuals, we identify T2D-related microbiota changes in the Danish and Indian study samples. In the present trans-ethnic study, we confirm that metformin changes the taxonomic profile and functional potential of the gut microbiota.
Recent studies have indicated an association of gut microbiota and microbial metabolites with type 2 diabetes mellitus (T2D). However, large-scale investigation of the gut microbiota of "prediabetic" ...(PD) subjects has not been reported. Identifying robust gut microbiome signatures of prediabetes and characterizing early prediabetic stages is important for the understanding of disease development and could be crucial in early diagnosis and prevention.
The current study performed amplification and sequencing on the variable regions (V1-V5) of the 16S rRNA genes to profile and compare gut microbiota of prediabetic individuals (N = 262) with normoglycemic individuals (N = 275) from two cohorts in India and Denmark. Similarly, fasting serum inflammatory biomarkers were profiled from the study participants.
After correcting for strong country-specific cohort effect, 16 operational taxonomic units (OTUs) including members from the genera Prevotella9, Phascolarctobacterium, Barnesiella, Flavonifractor, Tyzzerella_4, Bacteroides, Faecalibacterium, and Agathobacter were identified as enriched in normoglycaemic subjects with respect to the subjects with prediabetes using a negative binomial Wald test. We also identified 144 OTUs enriched in the prediabetic subjects, which included members from the genera Megasphaera, Streptococcus, Prevotella9, Alistipes, Mitsuokella, Escherichia/Shigella, Prevotella2, Vibrio, Lactobacillus, Alloprevotella, Rhodococcus, and Klebsiella. Comparative analyses of relative abundance of bacterial taxa revealed that the Streptococcus, Escherichia/Shigella, Prevotella2, Vibrio, and Alloprevotella OTUs exhibited more than fourfold enrichment in the gut microbiota of prediabetic subjects. When considering subjects from the two geographies separately, we were able to identify additional gut microbiome signatures of prediabetes. The study reports a probable association of Megasphaera OTU(s) with impaired glucose tolerance, which is significantly pronounced in Indian subjects. While the overall results confirm a state of proinflammation as early as in prediabetes, the Indian cohort exhibited a characteristic pattern of abundance of inflammatory markers indicating low-grade intestinal inflammation at an overall population level, irrespective of glycemic status.
The results present trans-ethnic gut microbiome and inflammation signatures associated with prediabetes, in Indian and Danish populations. The identified associations may be explored further as potential early indicators for individuals at risk of dysglycemia.
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