Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.

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Metformin and the gastrointestinal tract.

Drosophila neuroblasts, the stem cells of the developing fly brain, have emerged as a key model system for neural stem cell biology and have provided key insights into the mechanisms underlying asymmetric cell division and tumor formation. More recently, they have also been used to understand how neural progenitors can generate different neuronal subtypes over time, how their cell cycle entry and exit are coordinated with development, and how proliferation in the brain is spared from the growth restrictions that occur in other organs upon starvation. In this Primer, we describe the biology of Drosophila neuroblasts and highlight the most recent advances made using neuroblasts as a model system.

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Drosophila neuroblasts: a model for stem cell biology.

Dipeptidyl peptidase 4 (DPP4) is a glycoprotein of 110 kDa, which is ubiquitously expressed on the surface of a variety of cells. This exopeptidase selectively cleaves N-terminal dipeptides from a variety of substrates, including cytokines, growth factors neuropeptides, and the incretin hormones. Expression of DPP4 is substantially dysregulated in a variety of disease states including inflammation, cancer, obesity and diabetes. Since the incretin hormones GLP-1 and GIP are major regulators of post-prandial insulin secretion, inhibition of DPP4 by the gliptin family of drugs has gained considerable interest for the therapy of type 2 diabetic patients. In this review, we summarise the current knowledge on the DPP4 - incretin axis, and evaluate most recent findings on DPP4 inhibitors. Furthermore, DPP4 as a type II transmembrane protein is also known to be cleaved from the cell membrane involving different metalloproteases in a cell-type specific manner. Circulating, soluble DPP4 has been identified as a new adipokine which exerts both para- and endocrine effects. Recently, a novel receptor for soluble DPP4 has been identified and data are accumulating that the adipokine-related effects of DPP4 may play an important role in the pathogenesis of cardiovascular disease. Importantly, circulating DPP4 is augmented in obese and type 2 diabetic subjects and it may represent a molecular link between obesity and vascular dysfunction. A critical evaluation of the impact of circulating DPP4 is presented and the potential role of DPP4 inhibition at this level is also discussed.

DPP4 in Diabetes.

Dipeptidyl peptidase-4 (DPP-4), also known as the T-cell antigen CD26, is a multi-functional protein which, besides its catalytic activity, also functions as a binding protein and a ligand for a variety of extracellular molecules. It is an integral membrane protein expressed on cells throughout the body, but is also shed from the membrane and circulates as a soluble protein in the plasma. A large number of bioactive molecules can be cleaved by DPP-4 in vitro, but only a few of these have been demonstrated to be physiological substrates. One of these is the incretin hormone, glucagon-like peptide-1 (GLP-1), which plays an important role in the maintenance of normal glucose homeostasis, and DPP-4 has been shown to be the key enzyme regulating its biological activity. This pathway has been targeted pharmacologically through the development of DPP-4 inhibitors, and these are now a successful class of anti-hyperglycaemic agents used to treat type 2 diabetes (T2DM). DPP-4 may additionally influence metabolic control via its proteolytic effect on other regulatory peptides, but it has also been reported to affect insulin sensitivity, potentially mediated through its non-enzymatic interactions with other membrane proteins. Given that altered expression and activity of DPP-4 are associated with increasing body mass index and hyperglycaemia, DPP-4 has been proposed to play a role in linking obesity and the pathogenesis of T2DM by functioning as a local mediator of inflammation and insulin resistance in adipose and hepatic tissue. As well as these broader systemic effects, it has also been suggested that DPP-4 may be able to modulate β-cell function as part of a paracrine system involving GLP-1 produced locally within the pancreatic islets. However, while it is evident that DPP-4 has the potential to influence glycaemic control, its overall significance for the normal physiological regulation of glucose homeostasis in humans and its role in the pathogenesis of metabolic disease remain to be established.

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Physiology and Pharmacology of DPP-4 in Glucose Homeostasis and the Treatment of Type 2 Diabetes.

OBJECTIVE To study expression of the recently-identified adipokine dipeptidyl peptidase-4 (DPP4) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of patients with various BMIs and insulin sensitivities, as well as to assess circulating DPP4 in relation to obesity and insulin sensitivity. RESEARCH DESIGN AND METHODS DPP4 expression was measured in SAT and VAT from 196 subjects with a wide range of BMIs and insulin sensitivities. DPP4 release was measured ex vivo in paired biopsies from SAT and VAT as well as in vivo from SAT of lean and obese patients. Circulating DPP4 was measured in insulin-sensitive and insulin-resistant BMI-matched obese patients. RESULTS DPP4 expression was positively correlated with BMI in both SAT and VAT, with VAT consistently displaying higher expression than SAT. Ex vivo release of DPP4 from adipose tissue explants was higher in VAT than in SAT in both lean and obese patients, with obese patients displaying higher DPP4 release than lean controls. Net release of DPP4 from adipose tissue was also demonstrated in vivo with greater release in obese subjects than in lean subjects and in women than in men. Insulin-sensitive obese patients had significantly lower circulating DPP4 than did obesity-matched insulin-resistant patients. In this experiment, DPP4 positively correlated with the amount of VAT, adipocyte size, and adipose tissue inflammation. CONCLUSIONS DPP4, a novel adipokine, has a higher release from VAT that is particularly pronounced in obese and insulin-resistant patients. Our data suggest that DPP4 may be a marker for visceral obesity, insulin resistance, and the metabolic syndrome.

https://care.diabetesjournals.org/content/diacare/36/12/4083.full.pdf

Adipose Dipeptidyl Peptidase-4 and Obesity: Correlation with insulin resistance and depot-specific release from adipose tissue in vivo and in vitro

Background 
In a cross-sectional study we studied the fasting serum DPP-4 enzymatic activity (sDPP-4) and the insulin resistance index (HOMA2-IR) in gliptin naive patients with type 2 diabetes and in non-alcoholic fatty liver disease (NAFLD) and in healthy controls (CNTRL).


Methods and Findings 
sDPP-4 was measured by kinetic assay in 39 NAFLD (F/M:19/20, mean age: 47.42 yrs) and 82 type 2 diabetes (F/M:48/34, 62.8 yrs) patients and 26 (F/M:14/12, 35.3 yrs) controls. Definition of T2D group as patients with type 2 diabetes but without clinically obvious liver disease created non-overlapping study groups. Diagnosis of NAFLD was based on ultrasonography and the exclusion of other etiololgy. Patients in T2D and NAFLD groups were similarly obese. 75 g CH OGTT in 39 NAFLD patients: 24-NGT, 4-IGT or IFG (“prediabetes”), 11-type 2 diabetes. HOMA2-IR: CNTRL: 1.44; T2D-group: 2.62 (p = 0.046 vs CNTRL, parametric tests); NAFLD(NGTonly): 3.23 (p = 0.0013 vs CNTRL); NAFLD(IFG/IGT/type 2 diabetes): 3.82 (p<0.001 vs CNTRL, p = 0.049 vs 2TD group). sDPP-4 activity was higher in NAFLD both with NGT (mean:33.08U/L) and abnormal glucose metabolism (30.38U/L) than in CNTRL (25.89U/L, p<0.001 and p = 0.013) or in T2D groups (23.97U/L, p<0.001 and p = 0.004). Correlations in NAFLD among sDPP-4 and ALT: r = 0.4637,p = 0.0038 and γGT: r = 0.4991,p = 0.0017 and HOMA2-IR: r = 0.5295,p = 0.0026 and among HOMA2-IR and ALT: r = 0.4340,p = 0.0147 and γGT: r = 0.4128,p = 0.0210.


Conclusions 
The fasting serum DPP-4 activity was not increased in T2D provided that patients with liver disease were intentionally excluded. The high serum DPP-4 activities in NAFLD were correlated with liver tests but not with the fasting plasma glucose or HbA1C supporting that the excess is of hepatic origin and it might contribute to the speedup of metabolic deterioration. The correlation among γGT, ALT and serum DPP-4 activity and also between serum DPP-4 activity and HOMA2-IR in NAFLD strongly suggests that serum DPP-4 activity should be considered as a novel liver disease biomarker.

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Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker.

Dipeptidyl peptidase-4 (DPP-4) is involved in the metabolism of peptide hormones, T-cell activation and proliferation. In type 1 diabetes mellitus (T1DM) β-cell destruction involves a number of dysregulated T-cells. Our aim was to assess the serum DPP-4 activity and the lymphocyte membrane bound CD26 expression in patients with type 1 diabetes and healthy controls. Ninety-eight (T1DM: 48, F/M = 20/28, mean age: 34.4y; control: 50, F/M = 39/11 mean age: 32,4y) individuals were included. Fasting serum DPP-4 enzymatic activity, plasma glucose (FPG), CD26 expression on CD3+, CD4+ and CD8+ lymphocytes, HbA1c and body mass index (BMI) were assessed. ICA and GAD antibodies were assessed in the T1DM group. DPP-4 enzymatic activity was determined by kinetic enzyme assay, ICA and GAD were assessed by ELISA. Determination of the CD26 expression on CD3+, CD4+ and CD8+ lymphocytes was performed by flow-cytometric analysis. We found higher serum DPP-4 activity (Mean: T1DM: 30.069 U/L, control: 22.62 U/L, p < 0.0001) and decreased CD26 lymphocyte expression on all lymphocyte subpopulations in T1DM. Fasting serum DPP-4 activity was independent from the ICA or GAD status of patients with T1DM. Here we first present that the serum DPP-4 activity is increased and the lymphocyte membrane bound CD26 expression is decreased in type 1 diabetes. Decreased lymphocyte membrane bound CD26 expression in T1DM might be a novel part of the T-lymphocyte regulatory dysfunction observed in type 1 diabetes mellitus. These results might provide some basis for the clinical implication of DPP-4 inhibition in patients with T1DM.

Higher Serum DPP-4 Enzyme Activity and Decreased Lymphocyte CD26 Expression in Type 1 Diabetes

Aims Both diabetes mellitus and major depression are public health concerns, and the co-occurrence of these illnesses is highly frequent. Acting as a potential risk factor, hyperglycemia might facilitate the manifestation of depression in patients genetically predisposed to affective disorders. In the present study, candidate polymorphisms of the serotonin transporter, the tryptophan hydroxylase 2 ( TPH2 ) genes, as well as of the brain-derived neurotrophic factor BDNF , and the P2RX7 purinergic receptor genes were analyzed in Hungarian diabetic population. We assumed that genetic influence would be stronger on depressive symptoms in the “poor glycemic control” group (PC: HbA 1C  > 7%) compared to the “good glycemic control” group (GC: HbA 1C  ≤ 7%). Methods After excluding patients with current antidepressant medication, 218 diabetic patients' Hospital Anxiety and Depression Scale (HADS) scores were used in multivariate analysis of variance. Based on the HbA 1C levels, 81 patients were in the GC group, and 137 belonged to the PC group. Results After correcting for multiple testing, only the association of the P2RX7 Gln460Arg (rs2230912) polymorphism with depressive symptoms remained significant. Patients with the G-allele (Arg-variant) had higher scores on the HADS depression scales ( p  = 0.007). A gene x glycemic control interaction ( p  = 0.032) was observed on the anxiety scale at the TPH2 promoter polymorphism: the -703T-allele decreased anxiety scores only in the GC group ( p  = 0.008). Conclusions Our results support the role of the P2RX7 rs2230912 G-allele in the development of depression and emphasize the importance of good glycemic control, acting as a potential protective factor in diabetic patients.

P2RX7 Gln460Arg polymorphism is associated with depression among diabetic patients.

Patients with diabetes are approximately 1.5 times more likely to experience cognitive decline than individuals without diabetes mellitus. Most of the data suggest that patients with diabetes have reduced performance in numerous domains of cognitive function. In patients with type 1 diabetes, specific and global deficits involving speed of psychomotor efficiency, information processing, mental flexibility, attention, and visual perception seem to be present, while in patients with type 2 diabetes an increase in memory deficits, a reduction in psychomotor speed, and reduced frontal lobe (executive) functions have been found. The complex pathophysiology of changes in the central nervous system in diabetes has not yet been fully elucidated. It is important to consider the patient's age at the onset of diabetes, the glycemic control status, and the presence of diabetic complications. Neurological consequences of diabetes appear parallel to those observed in the aging brain. Neuroimaging studies highlight several structural cerebral changes, cortical and subcortical atrophy, beside increased leukoaraiosis that occurs in association with diabetes. There is supporting evidence from many hypotheses to explain the pathophysiology of cognitive decline associated with diabetes. The main hypotheses pointing to the potential, implied mechanisms involve hyperglycemia, hypoglycemia, microvascular disease, insulin resistance, hyperinsulinism, hyperphosphorylation of tau protein, and amyloid-β deposition.

Changes in cognitive function in patients with diabetes mellitus

Research in genetics and immunology was going on separate strands for a long time. Type 1 diabetes mellitus might not be characterized with a single pathogenetic factor. It develops when a susceptible individual is exposed to potential triggers in a given sequence and timeframe that eventually disarranges the fine-tuned immune mechanisms that keep autoimmunity under control in health. Genomewide association studies have helped to understand the congenital susceptibility, and hand-in-hand with the immunological research novel paths of immune dysregulation were described in central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells. Epigenetic factors are contributing to the immune dysregulation. The interplay between genetic susceptibility and potential triggers is likely to play a role at a very early age and gradually results in the loss of balanced autotolerance and subsequently in the development of the clinical disease. Genetic susceptibility, the impaired elimination of apoptotic β-cell remnants, altered immune regulatory functions, and environmental factors such as viral infections determine the outcome. Autoreactivity might exist under physiologic conditions and when the integrity of the complex regulatory process is damaged the disease might develop. We summarized the immune regulatory mechanisms that might have a crucial role in disease pathology and development.

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Tímea Varga

Papers

Serum dipeptidyl peptidase-4 activity in insulin resistant patients with non-alcoholic fatty liver disease: a novel liver disease biomarker.

Higher Serum DPP-4 Enzyme Activity and Decreased Lymphocyte CD26 Expression in Type 1 Diabetes

P2RX7 Gln460Arg polymorphism is associated with depression among diabetic patients.

Changes in cognitive function in patients with diabetes mellitus

Altered Immune Regulation in Type 1 Diabetes