Clinical pharmacology of antidiabetic drugs: What can be expected of their use?

The pharmacotherapy of type 2 diabetes mellitus (T2DM) has markedly evolved in the last two decades. Classical antidiabetic agents (sulphonylureas, metformin, insulin) are now in competition with new glucose-lowering medications. Alpha-glucosidase inhibitors and thiazolidinediones (glitazones) were not able to replace older agents, because of insufficient efficacy and/or poor tolerability/safety. In contrast, incretin-based therapies, both dipeptidyl peptidase-4 inhibitors (DPP-4is or gliptins, oral agents) and glucagon-like peptide-1 receptor agonists (GLP-1RAs, subcutaneous injections) are a major breakthrough in the management of T2DM. Because they are not associated with hypoglycaemia and weight gain, DPP-4is tend to replace sulphonylureas as add-on to metformin while GLP-1RAs tend to replace basal insulin therapy after failure of oral therapies. Furthermore, placebo-controlled cardiovascular outcome trials demonstrated neutrality for DPP-4is, but cardiovascular protection for GLP-1RAs in patients with T2DM at high cardiovascular risk. More recently sodium-glucose cotransporter 2 inhibitors (SGLT2is or gliflozins, oral agents) also showed cardiovascular protection, especially a reduction in hospitalization for heart failure, as well as a renal protection in patients with and without T2DM, at high cardiovascular risk, with established heart failure and/or with chronic kidney disease. Thus, GLP-1RAs and SGLT2is are now considered as preferred drugs in T2DM patients with or at high risk of atherosclerotic cardiovascular disease whereas SGLT2is are more specifically recommended in patients with or at risk of heart failure and renal (albuminuric) disease. The management of T2DM is moving from a glucocentric approach to a broader strategy focusing on all risk factors, including overweight/obesity, and to an organ-disease targeted personalized approach.     

Incretin manipulation in diabetes management

Incretin-based therapies have revolutionized the medical management of type 2 diabetes mellitus(T2DM) in the 21 st century. Glucagon-like peptide-1(GLP-1) suppresses appetite and gastric motility, and has trophic effects on pancreas, cardio-protective and renal effects. GLP-1 analogues and dipeptidyl peptidase-4 inhibitors form the incretin-based therapies. Significant reduction of hemoglobin A1 c when used as monotherapy and in combination regimens, favorable effects on body weight, and low risk of hypoglycemia are their unique therapeutic benefits. Their safety and tolerability are comparable to other anti-diabetic medications. Concern about elevated risk of pancreatitis has been discarded by two recent meta-analyses. This article discusses the therapeutic manipulation of incretin system for the management of T2 DM.     

Comparable early changes in gastrointestinal hormones after sleeve gastrectomy and Roux-En-Y gastric bypass surgery for morbidly obese type 2 diabetic subjects

Background

Sleeve gastrectomy (SG) and Roux-en-Y gastric bypass (RYGBP) are associated with similar type 2 diabetes mellitus (T2DM) resolution rates for morbidly obese subjects. However, the mechanisms underlying the resolution of T2DM after SG have not been clarified to date. This study aimed to compare the early changes in gastrointestinal hormones involved in insulin and glucagon secretion in morbidly obese T2DM subjects undergoing SG or RYGBP.

Methods

This prospective study investigated 12 subjects with T2DM who had undergone SG (n?=?6) or RYGBP (n?=?6). Five body mass index (BMI)-matched obese non-diabetic subjects and five BMI-matched obese diabetic subjects served as control subjects. Glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and GLP-2 were determined after a standardized mixed liquid meal before surgery and 6?weeks afterward.

Results

After 6?weeks, five of the six subjects in each surgical group presented with T2DM remission, although the area under the curve (AUC)_0–120 of glucose was greater than that of the non-diabetic control subjects (P?0–120 of GLP-1 (P?P?P?Conclusions The data show that in a cohort of morbidly obese T2DM subjects, SG and RYGBP are associated with an early improvement in glucose tolerance, similar changes in insulin and glucagon secretion, and a similar GLP-1, GIP, and GLP-2 response to a standardized mixed liquid meal.     

Relevance of beta-cell function for improved glycemic control after gastric bypass surgery

BackgroundResidual beta-cell function and gastrointestinal hormones have been suggested as relevant determinants of improved glycemic control ensuing Roux-en-Y gastric bypass (RYGB). The objective of this study was to compare the glycemic control up to 24 months after RYGB in C-peptide negative morbidly obese (MO) type 1 diabetes mellitus (T1 DM) women (n = 7) and C-peptide positive (>.6 ng/mL) MO women with type 2 diabetes mellitus (T2 DM, n = 7) on basal-bolus insulin therapy. The glucagon-like peptide 1 (GLP-1) and glucagon response to a mixed meal challenge were also compared between groups.MethodsPercent excess weight loss (%EWL), HbA_1c, and daily insulin dose (DID) after RYGB were compared between groups. The GLP-1 and glucagon response (area under the curve 0–120 minutes) after a mixed meal at last follow-up visit were also compared.ResultsAt 24-months, marked %EWL was observed in women with T1 DM and women with T2 DM (mean±standard error, 82.6%±11.3% and 87.4%±30.5%, respectively; P = .722]. In women with T1 DM, HbA_1c (4 months, P<.05) and DID improved transiently (P<.05, up to 8 months) but were comparable to baseline thereafter (HbA_1c: baseline, 8.3±1.2 and 24 months, 8.2±.9, P = 1.00; DID: baseline, .61±.17 and 24 months .62±.12 IU/kg/d, P = 1.00]. In contrast, in MO women with T2 DM, HbA_1c decreased significantly throughout follow–up, with 2 patients presenting diabetes remission and all but one an HbA_1c<7% at 24 months. The GLP-1 response was comparable between groups (P = .612), and was not accompanied by suppression of the glucagon response to meal intake.ConclusionsIn the absence of residual beta-cell, RYGB results in no significant benefit on glycemic control, despite a marked response of GLP-1 to meal intake.     

Hormone changes and diabetes resolution after biliopancreatic diversion and laparoscopic sleeve gastrectomy: a comparative prospective study

BackgroundBiliopancreatic diversion (BPD) is the most effective bariatric procedure in terms of weight loss and remission of diabetes type 2 (T2DM), but it is accompanied by nutrient deficiencies. Sleeve gastrectomy (SG) is a relatively new operation that has shown promising results concerning T2DM resolution and weight loss. The objective of this study was to evaluate and compare prospectively the effects of BPD long limb (BPD) and laparoscopic SG on fasting, and glucose-stimulated insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1) secretion and also on remission of T2DM, hypertension, and dyslipidemia in morbidly obese patients with T2DM.MethodsTwelve patients (body mass index [BMI] 57.6±9.9 kg/m²) underwent BPD and 12 (BMI 43.7±2.1 kg/m²) underwent SG. All patients had T2DM and underwent an oral glucose tolerance test (OGTT) before and 1, 3, and 12 months after surgery.ResultsBMI decreased more after BPD, but percent excess weight loss (%EWL) was similar in both groups (P = .8) and T2DM resolved in all patients at 12 months. Insulin sensitivity improved more after BPD than after SG (P = .003). Blood pressure, total and LDL cholesterol decreased only after BPD (P<.001). Triglycerides decreased after either operation, but HDL increased only after SG (P<.001). Fasting ghrelin did not change after BPD (P = .2), but decreased markedly after SG (P<.001). GLP-1 and PYY responses during OGTT were dramatically enhanced after either procedure (P = .001).ConclusionsSG was comparable to BPD in T2DM resolution but inferior in improving dyslipidemia and blood pressure. SG and BPD enhanced markedly PYY and GLP-1 responses but only SG suppressed ghrelin levels.     

Incretin-based therapies in prediabetes: Current evidence and future perspectives

The prevalence of type 2 diabetes(T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance(NGT) and the clinical entity of T2 D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2 D. The huge burden resulting from the complications of T2 D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1(GLP-1) receptor agonists, on β-cell function in patients with T2 D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2 D.     

Marked Expansion of Exocrine and Endocrine Pancreas With Incretin Therapy in Humans With Increased Exocrine Pancreas Dysplasia and the Potential for Glucagon-Producing Neuroendocrine Tumors

Controversy exists regarding the potential regenerative influences of incretin therapy on pancreatic β-cells versus possible adverse pancreatic proliferative effects. Examination of pancreata from age-matched organ donors with type 2 diabetes mellitus (DM) treated by incretin therapy (n = 8) or other therapy (n = 12) and nondiabetic control subjects (n = 14) reveals an ∼40% increased pancreatic mass in DM treated with incretin therapy, with both increased exocrine cell proliferation (P < 0.0001) and dysplasia (increased pancreatic intraepithelial neoplasia, P < 0.01). Pancreata in DM treated with incretin therapy were notable for α-cell hyperplasia and glucagon-expressing microadenomas (3 of 8) and a neuroendocrine tumor. β-Cell mass was reduced by ∼60% in those with DM, yet a sixfold increase was observed in incretin-treated subjects, although DM persisted. Endocrine cells costaining for insulin and glucagon were increased in DM compared with non-DM control subjects (P < 0.05) and markedly further increased by incretin therapy (P < 0.05). In conclusion, incretin therapy in humans resulted in a marked expansion of the exocrine and endocrine pancreatic compartments, the former being accompanied by increased proliferation and dysplasia and the latter by α-cell hyperplasia with the potential for evolution into neuroendocrine tumors.Type 2 diabetes mellitus (DM) is characterized by defective insulin secretion in the setting of insulin resistance, leading to hyperglycemia. This defect in insulin secretion is accompanied by a deficit in β-cell mass. However, the extent and relevance of this β-cell deficit has been questioned, in part due to the paucity of human pancreatic studies as well as to methodological differences among such efforts (1–3). Therapeutic hope for DM has recently been raised by the introduction of a glucagon-like peptide-1 (GLP-1) mimetic class of drugs widely referred to as incretins. Interestingly, beyond their effects on improved metabolic regulation, GLP-1 mimetic therapy was also noted to induce β-cell regeneration in rodents, thus portending the remarkable notion that the deficit in β-cell mass in DM might be overcome with such agents (4–7). However, given this ability was most evident in the period coincident with the postnatal expansion of β-cell mass in rodents, questions arose as to the relevance of this property of GLP-1 in adult humans (8,9). Moreover, β-cell replication was not detected in human islets exposed to high concentrations of GLP-1 in vitro (10). In contrast, there are concerns that the proproliferative actions of GLP-1 might induce deleterious effects on the exocrine pancreas, in which the capacity for the proproliferative actions of GLP-1 appears to be better retained into adult life (5,11,12).To address this, we analyzed a series of high-quality (i.e., transplant grade) human pancreata obtained from brain-dead organ donors with and without DM, including a subgroup of the latter who underwent ≥1 year of incretin therapy (13). Our goals were to confirm that β-cell mass was indeed decreased with DM overall and to establish whether incretin therapy induced an expansion of the endocrine and/or exocrine pancreas.     

A new stable GIP–Oxyntomodulin hybrid peptide improved bone strength both at the organ and tissue levels in genetically-inherited type 2 diabetes mellitus

Obesity and type 2 diabetes mellitus (T2DM) progress worldwide with detrimental effects on several physiological systems including bone tissue mainly by affecting bone quality. Several gut hormones analogues have been proven potent in ameliorating bone quality. In the present study, we used the leptin receptor-deficient db/db mice as a model of obesity and severe T2DM to assess the extent of bone quality alterations at the organ and tissue levels. We also examined the beneficial effects of gut hormone therapy in this model by using a new triple agonist ([d-Ala²]GIP–Oxm) active at the GIP, GLP-1 and glucagon receptors. As expected, db/db mice presented with dramatic alterations of bone strength at the organ level associated with deterioration of trabecular and cortical microarchitectures and an augmentation in osteoclast numbers. At the tissue level, these animals presented also with alterations of bone strength (reduced hardness, indentation modulus and dissipated energy) with modifications of tissue mineral distribution, collagen glycation and collagen maturity. The use of [d-Ala²]GIP–Oxm considerably improved bone strength at the organ level with modest effects on trabecular microarchitecture. At the tissue level, [d-Ala²]GIP–Oxm ameliorated bone strength reductions with positive effects on collagen glycation and collagen maturity. This study provides support for including gut hormone analogues as possible new therapeutic strategies for improving bone quality in bone complications associated to T2DM.     

GLP-1 Response to a Mixed Meal: What Happens 10 Years after Roux-en-Y Gastric Bypass (RYGB)?

Background

Oral meal consumption increases glucagon-like peptide 1 (GLP-1) release which maintains euglycemia by increasing insulin secretion. This effect is exaggerated during short-term follow-up of Roux-en-y gastric bypass (RYGB). We examined the durability of this effect in patient with type 2 diabetes (T2DM) >10?years after RYGB.

Methods

GLP-1 response to a mixed meal in the 10-year post-RYGB group (n?=?5) was compared to lean (n?=?9), obese (n?=?6), and type 2 diabetic (n?=?10) controls using a cross-sectional study design. Analysis of variance (ANOVA) was used to evaluate GLP-1 response to mixed meal consumption from 0 to 300?min, 0?C20?min, 20?C60?min, and 60?C300?min, respectively. Weight, insulin resistance, and T2DM were also assessed.

Results

GLP-1 response 0?C300?min in the 10-year post-RYGB showed a statistically significant overall difference (p?=?0.01) compared to controls. Furthermore, GLP-1 response 0?C20?min in the 10-year post-RYGB group showed a very rapid statistically significant rise (p?=?0.035) to a peak of 40?pM. GLP-1 response between 20 and 60?min showed a rapid statistically significant (p?=?0.041) decline in GLP-1 response from ~40?pM to 10?pM. GLP-1 response in the 10-year post-RYGB group from 60 to 300?min showed no statistically significant difference from controls. BMI, HOMA, and fasting serum glucose before and >10?years after RYGB changed from 59.9????40.4, 8.7????0.88, and 155.2????87.6?mg/dl, respectively, and were statistically significant (p?Conclusions An exaggerated GLP-1 response was noted 10?years after RYGB, strongly suggesting a durability of this effect. This phenomenon may play a key role in maintaining type 2 diabetes remission and weight loss after RYGB.     

Impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass on the hypoglycemic effect and glucagon-like peptide-1 in rats with type 2 diabetes mellitus

Background

The impact of the hepatic branch of the vagus and Roux-en-Y gastric bypass (RYGB) on the hypoglycemic effect and glucagon-like peptide-1 (GLP-1) in rats with type 2 diabetes mellitus (T2DM) was investigated, and interactions were preliminarily analyzed.

Methods

A total of 45 rats with T2DM were divided into four groups: sham operation (S, n = 10), sham operation with the hepatic branch of the vagus resected (SV, n = 11), RYGB (n = 12), and RYGB without preservation of the vagus (RYGBV, n = 12). Body mass, fasting blood glucose (FBG), fasting serum insulin, and concentrations of fasting serum GLP-1 were examined in the first, second, fourth, and eighth week before and after surgery. The effects of RYGB and the hepatic branch of the vagus on GLP-1 levels in the eighth postoperative week were also analyzed.

Results

RYGB caused a significant reduction in the weight of rats with T2DM (P < 0.05), improved the levels of serum GLP-1 and insulin (P < 0.05), and decreased FBG level (P < 0.05). Retention of the hepatic branch of the vagus maintained weight reduction for a longer period (P < 0.05) and increased the levels of serum GLP-1 and insulin (P < 0.05), but had no impact on FBG level (P > 0.05).

Conclusions

RYGB had better therapeutic efficacy in rats with T2DM. Care should be taken during RYGB surgery to preserve the hepatic branch of the vagus.     

Diabetes,Drug Treatment,and Mortality in COVID-19: A Multinational Retrospective Cohort Study

Patients with type 2 diabetes mellitus (T2DM) are at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes possibly because of dysregulated inflammatory responses. Glucose-regulating medications, such as glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, and pioglitazone, are known to have anti-inflammatory effects that may improve outcomes in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a multinational retrospective cohort study, we used the TriNetX COVID-19 Research Network of 56 large health care organizations to examine these medications in relation to the incidence of hospital admissions, respiratory complications, and mortality within 28 days after a COVID-19 diagnosis. After matching for age, sex, race, ethnicity, BMI, and significant comorbidities, use of GLP-1R agonists and/or pioglitazone was associated with significant reductions in hospital admissions (GLP-1R: 15.7% vs. 23.5%, risk ratio [RR] 0.67 [95% CI 0.57–0.79; P < 0.001]; pioglitazone: 20.0% vs. 28.2%; RR 0.71 [95% CI 0.54–0.93; P = 0.01]). Use of GLP-1R agonists was also associated with reductions in respiratory complications (15.3% vs. 24.9%, RR 0.62 [95% CI 0.52–0.73]; P < 0.001) and incidence of mortality (1.9% vs. 3.3%, RR 0.58 [95% CI 0.35–0.97]; P = 0.04). Use of DPP-4 inhibitors was associated with a reduction in respiratory complications (24.0% vs. 29.2%, RR 0.82 [95% CI 0.74–0.90]; P < 0.001), and continued use of DPP-4 inhibitors after hospitalization was associated with a decrease in mortality compared with those who discontinued use (9% vs. 19%, RR 0.45 [95% CI 0.28–0.72]; P < 0.001). In conclusion, use of glucose-regulating medications, such as GLP-1R agonists, DPP-4 inhibitors, or pioglitazone, may improve COVID-19 outcomes for patients with T2DM; randomized clinical trials are needed to further investigate this possibility.     

Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.     

Re-emergence of diabetes after gastric bypass in patients with mid- to long-term follow-up

BackgroundStudies have shown that type 2 diabetes (T2DM) improves or resolves shortly after Roux-en-Y gastric bypass (RYGB). Few data are available on T2DM recurrence or the effect of weight regain on T2DM status.MethodsA review of 42 RYGB patients with T2DM and ≥3 years of follow-up and laboratory data was performed. Postoperative weight loss and T2DM status was assessed. Recurrence or worsening was defined as hemoglobin A1c >6.0% and fasting glucose >124 mg/dL and/or medication required after remission or improvement. Patients whose T2DM recurred or worsened were compared with those whose did not, and patients whose T2DM improved were compared with those whose T2DM resolved.ResultsT2DM had either resolved or improved in all patients (64% and 36%, respectively); 24% (10) recurred or worsened. The patients with recurrence or worsening had had a lower preoperative body mass index than those without recurrence or worsening (47.9 versus 52.9 kg/m2; P = .05), regained a greater percentage of their lost weight (37.7% versus 15.4%; P = .002), had a greater weight loss failure rate (63% versus 14%; P = .03), and had greater postoperative glucose levels (138 versus 102 mg/dL; P = .0002). Patients who required insulin or oral medication before RYGB were more likely to experience improvement rather than resolution (92% versus 8%, P ≤.0001; and 85% versus 15%; P = .0006, respectively).ConclusionOur results have shown that beyond 3 years after RYGB, the incidence of T2DM recurrence or worsening in patients with initial resolution or improvement was significant. In our patients, a greater likelihood of recurrence or worsening of T2DM was associated with a lower preoperative body mass index. Before widespread acceptance of bariatric surgery as a definitive treatment for those with T2DM can be achieved, additional study of this recurrence phenomenon is indicated.     

Rise in Postprandial GLP-1 Levels After Roux-en-Y Gastric Bypass: Involvement of the Vagus Nerve–Spleen Anti-inflammatory Axis in Type 2 Diabetic Rats

Purpose

The mechanism underlying postprandial glucagon-like peptide-1 (GLP-1) changes after metabolic surgery remains mostly unclarified. This investigation aimed to address whether the vagus nerve–spleen anti-inflammatory axis is involved in the rise in postprandial GLP-1 levels in type 2 diabetes mellitus (T2DM) rats following metabolic surgery.

Materials and Methods

T2DM rat model was established with a high-fat diet and a low dose of streptozotocin and subjected to Roux-en-Y gastric bypass (RYGB) and splenic denervation. A mixed-meal tolerance test for postprandial GLP-1 response was performed. TNF-α in the plasma, spleen, and ileum was measured by ELISA, and alpha 7 nicotinic acetylcholine receptor (α7nAChR) expression in the spleen was analyzed by Western blot.

Results

Postprandial GLP-1 improvement by RYGB was accompanied by the reduction of TNF-α levels in spleen and ileum and up-regulation of splenic α7nAChR in T2DM rats. Splenic denervation abrogates a rise in postprandial GLP-1 levels in response to the mixed-meal challenge, along with higher TNF-α levels in spleen and ileum and down-regulation of splenicα7nAChR, compared with denervated sham rats.

Conclusion

Our results reveal that the vagus nerve–spleen anti-inflammatory axis mediates the rise of postprandial GLP-1 response after RYGB through lowering TNF-α contents in the intestinal tissue in T2DM rats.

     

Prevention of macrovascular complications in patients with type 2 diabetes mellitus: Review of cardiovascular safety and efficacy of newer diabetes medications

Lack of conclusive beneficial effects of strict glycemic control on macrovascular complications has been very frustrating for clinicians involved in care of patients with diabetes mellitus(DM). Highly publicized controversy surrounding cardiovascular(CV) safety of rosiglitazone resulted in major changes in United States Food and Drug Administration policy in 2008 regarding approval process of new antidiabetic medications, which has resulted in revolutionary data from several large CV outcome trials over the last few years. All drugs in glucagon-like peptide-1 receptor agonist(GLP-1 RA) and sodium-glucose cotransporter-2(SGLT-2) inhibitor classes have shown to be CV safe with heterogeneous results on CV efficacy. Given twofold higher CV disease mortality in patients with DM than without DM, GLP-1 RAs and SGLT-2-inhibitors are important additions to clinician's armamentarium and should be second line-therapy particularly in patients with T2 DM and established atherosclerotic CV disease or high risks for CV disease. Abundance of data and heterogeneity in CV outcome trials results can make it difficult for clinicians, particularly primary care physicians, to stay updated with all the recent evidence. The scope of this comprehensive review will focus on all major CV outcome studies evaluating CV safety and efficacy of GLP-1 RAs and SGLT-2 inhibitors.     

Transient receptor potential vanilloid 1 activation enhances gut glucagon-like peptide-1 secretion and improves glucose homeostasis

Type 2 diabetes mellitus (T2DM) is rapidly prevailing as a serious global health problem. Current treatments for T2DM may cause side effects, thus highlighting the need for newer and safer therapies. We tested the hypothesis that dietary capsaicin regulates glucose homeostasis through the activation of transient receptor potential vanilloid 1 (TRPV1)-mediated glucagon-like peptide-1 (GLP-1) secretion in the intestinal cells and tissues. Wild-type (WT) and TRPV1 knockout (TRPV1(-/-)) mice were fed dietary capsaicin for 24 weeks. TRPV1 was localized in secretin tumor cell-1 (STC-1) cells and ileum. Capsaicin stimulated GLP-1 secretion from STC-1 cells in a calcium-dependent manner through TRPV1 activation. Acute capsaicin administration by gastric gavage increased GLP-1 and insulin secretion in vivo in WT but not in TRPV1(-/-) mice. Furthermore, chronic dietary capsaicin not only improved glucose tolerance and increased insulin levels but also lowered daily blood glucose profiles and increased plasma GLP-1 levels in WT mice. However, this effect was absent in TRPV1(-/-) mice. In db/db mice, TRPV1 activation by dietary capsaicin ameliorated abnormal glucose homeostasis and increased GLP-1 levels in the plasma and ileum. The present findings suggest that TRPV1 activation-stimulated GLP-1 secretion could be a promising approach for the intervention of diabetes.     

Early Improvement of Postprandial Lipemia After Bariatric Surgery in Obese Type 2 Diabetic Patients

Background

Bariatric surgery (BS) is able to positively influence fasting lipid profile in obese type 2 diabetic patients (T2DM), but no data is available on the impact of BS on postprandial lipid metabolism neither on its relation with incretin hormones. We evaluated the short-term (2 weeks) effects of BS on fasting and postprandial lipid metabolism in obese T2DM patients and the contribution of changes in active GLP-1.

Methods

We studied 25 obese T2DM patients (age?=?46?±?8 years, BMI?=?44?±?7 kg/m²), of which 15 underwent sleeve gastrectomy and 10 underwent gastric bypass. Lipid and incretin hormone concentrations were evaluated for 3 h after ingestion of a liquid meal before and 2 weeks after BS.

Results

After BS, there was a significant reduction in body weight (p?<?0.001), fasting plasma glucose (p?<?0.001), fasting plasma insulin (p?<?0.05), HOMA-IR (p?<?0.001), and fasting plasma lipids (p?<?0.05). The meal response of plasma triglycerides, total cholesterol, and HDL cholesterol was significantly lower compared to pre-intervention (p?<?0.05, p?<?0.001). In particular, the incremental area under the curve (IAUC) of plasma triglycerides decreased by 60 % (p?<?0.005). The meal-stimulated response of active GLP-1 increased, reaching a statistical significance (p?<?0.001).

Conclusions

BS leads to an early improvement of fasting and postprandial lipemia. The fall in fasting triglycerides is associated with an improvement of insulin resistance, while the reduction of postprandial lipemia is likely related to reduced intestinal lipid absorption consequent to bariatric surgery.     

Enterotrophic effects of glucagon-like peptide 2 are enhanced by neurotensin

Combination therapy with enterotrophic agents may be useful in patients with the short bowel syndrome. The gut hormones neurotensin (NT) and glucagon-hke peptide 2 (GLP-2) are potent enterotrophic fattors when administered alone; however, their combined effects are not known. Using a GLP-2-producing tumor (STC-1), we determined whether administration of NT enhances the effect of GLP-2 on intestinal growth. Athymic mice were injected with STC-1 cells (6 × 10⁶) subcutaneously. Twenty-three days after STC-1 implantation, mice received either NT (300 μg/kg or 600 μg/kg) or saline solution (control) subcutaneously three times a day for 6 days. Two groups of tumor-free mice received either saline or NT for 6 days. At sacrifice, jejunum and ileum were collected, weighed, and analyzed for DNA and protein content. In the jejunum, NT combined with GLP-2 (from STC-1) increased weight, protein content (markers of mucosal hypertrophy), and DNA content (a marker of mucosal hyperplasia), compared to either NT or GLP-2 alone. In the ileum, the combination of NT and GLP-2 significantly increased weight and/or protein content compared to NT or GLP-2 alone. Administration of NT enhances the enterotrophic effects of GLP-2, augmenting hypertrophy of the entire small bowel and hyperplasia of the jejunum. The combination of NT and GLP-2 may be useful to enhance intestinal growth in patients with the short bowel syndrome. Supported in part by National Institutes of Health grants PO1 DK356O8, ROI DK48345, ROI AG10885, and T32 DK07633. Presented in part at the Surgical Forum of the American College of Surgeons, Chicago, Ill., October 12–17, 1997; and at the Thirty-Ninth Annual Meeting of The Society for Surgery of the Alimentary Tract, New Orleans, La., May 17–20, 1998.     

The evolving place of incretin-based therapies in type 2 diabetes

Treatment options for type 2 diabetes based on the action of the incretin hormone glucagon-like peptide-1 (GLP-1) were first introduced in 2005. These comprise the injectable GLP-1 receptor agonists solely acting on the GLP-1 receptor on the one hand and orally active dipeptidyl-peptidase inhibitors (DPP-4 inhibitors) raising endogenous GLP-1 and other hormone levels by inhibiting the degrading enzyme DPP-4. In adult medicine, both treatment options are attractive and more commonly used because of their action and safety profile. The incretin-based therapies stimulate insulin secretion and inhibit glucagon secretion in a glucose-dependent manner and carry no intrinsic risk of hypoglycaemia. GLP-1 receptor agonists allow weight loss, whereas DPP-4 inhibitors are weight neutral. This review gives an overview of the mechanism of action and the substances and clinical data available.