incretins and Hyperinsulinism

Equine insulin dysregulation (ID) comprises amplified insulin responses to oral carbohydrates or insulin resistance, or both, which leads to sustained or periodic hyperinsulinaemia. Hyperinsulinaemia is important in horses because of its clear association with laminitis risk, and the gravity of this common sequela justifies the need for a better understanding of insulin and glucose homoeostasis in this species. Post-prandial hyperinsulinaemia is the more commonly identified component of ID and is diagnosed using tests that include an assessment of the gastrointestinal tract (GIT). There are several factors present in the GIT that either directly, or indirectly, enhance insulin secretion from the endocrine pancreas, and these factors are collectively referred to as the enteroinsular axis (EIA). A role for key components of the EIA, such as the incretin peptides glucagon-like peptide-1 and 2, in the pathophysiology of ID has been investigated in horses. By comparison, the function (and even existence) of many EIA peptides of potential importance, such as glicentin and oxyntomodulin, remains unexplored. The incretins that have been examined all increase insulin responses to oral carbohydrate through one or more mechanisms. This review presents what is known about the EIA in horses, and discusses how it might contribute to ID, then compares this to current understanding derived from the extensive studies undertaken in other species. Future directions for research are discussed and knowledge gaps that should be prioritised are suggested.

Topics: Animals; Glucose; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Insulin Resistance; Metabolic Syndrome

Glucose levels in blood must be constantly maintained within a tight physiological range to sustain anabolism. Insulin regulates glucose homeostasis via its effects on glucose production from the liver and kidneys and glucose disposal in peripheral tissues (mainly skeletal muscle). Blood levels of glucose are regulated simultaneously by insulin-mediated rates of glucose production from the liver (and kidneys) and removal from muscle; adipose tissue is a key partner in this scenario, providing nonesterified fatty acids (NEFA) as an alternative fuel for skeletal muscle and liver when blood glucose levels are depleted. During sleep at night, the gradual development of insulin resistance, due to growth hormone and cortisol surges, ensures that blood glucose levels will be maintained within normal levels by: (a) switching from glucose to NEFA oxidation in muscle; (b) modulating glucose production from the liver/kidneys. After meals, several mechanisms (sequence/composition of meals, gastric emptying/intestinal glucose absorption, gastrointestinal hormones, hyperglycemia mass action effects, insulin/glucagon secretion/action, de novo lipogenesis and glucose disposal) operate in concert for optimal regulation of postprandial glucose fluctuations. The contribution of the liver in postprandial glucose homeostasis is critical. The liver is preferentially used to dispose over 50% of the ingested glucose and restrict the acute increases of glucose and insulin in the bloodstream after meals, thus protecting the circulation and tissues from the adverse effects of marked hyperglycemia and hyperinsulinemia.

Topics: Adipose Tissue; Blood Glucose; Fasting; Fatty Acids, Nonesterified; Gastric Emptying; Glucose; Homeostasis; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Incretins; Insulin; Insulin Resistance; Kidney; Liver; Meals; Muscle, Skeletal; Postprandial Period

Hypoglycaemia after gastric bypass can be severe, but is uncommon, and is sometimes only revealed through monitoring glucose concentrations. The published literature is limited by the heterogeneity of the criteria used for diagnosis, arguing in favour of the Whipple triad with a glycaemia threshold of 55 mg/dl as the diagnostic reference. Women who lost most of their excess weight after gastric bypass, long after the surgery was performed, and who did not have diabetes before surgery are at the greatest risk. In this context, hypoglycaemia results from hyperinsulinism, which is either generated by pancreas anomalies (nesidioblastosis) and/or caused by an overstimulation of β cells by incretins, mainly glucagon-like peptide-1 (GLP-1). Glucose absorption is both accelerated and increased because of the direct communication between the gastric pouch and the jejunum. This is a post-surgical exaggeration of a natural adaptation that is seen in patients who have not undergone surgery in whom glucose is infused directly into the jejunum. There is not always a correspondence between symptoms and biological traits; however, hyperinsulinism is constant if hypoglycaemia is severe and there are neuroglucopenic symptoms. The treatment relies firstly on changes in eating habits, splitting food intake into five to six daily meals, slowing gastric emptying, reducing the glycaemic load and glycaemic index of foods, using fructose and avoiding stress at meals. Pharmacological treatment with acarbose is efficient, but other drugs still need to be validated in a greater number of subjects (insulin, glucagon, calcium channel blockers, somatostatin analogues and GLP-1 analogues). Lastly, if the surgical option has to be used, the benefits (efficient symptom relief) and the risks (weight regain, diabetes) should be weighed carefully.

Topics: Acarbose; Adaptation, Physiological; Adult; Blood Glucose; Diet Therapy; Female; Gastric Bypass; Glucagon-Like Peptide 1; Glycoside Hydrolase Inhibitors; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Incretins; Insulin-Secreting Cells; Jejunum; Male

Nopal is a plant used in traditional Mexican medicine to treat diabetes. However, there is insufficient scientific evidence to demonstrate whether nopal can regulate postprandial glucose. The purpose for conducting this study was to evaluate the glycemic index, insulinemic index, glucose-dependent insulinotropic peptide (GIP) index, and the glucagon-like peptide 1 (GLP-1) index, and the effect of nopal on patients with type 2 diabetes after consumption of a high-carbohydrate breakfast (HCB) or high-soy-protein breakfast (HSPB) on the postprandial response of glucose, insulin, GIP, GLP-1, and antioxidant activity. In study 1, the glycemic index, insulinemic index, GIP index, and GLP-1 index were calculated for seven healthy participants who consumed 50 g of available carbohydrates from glucose or dehydrated nopal. In study 2, 14 patients with type 2 diabetes consumed nopal in HCB or HSPB with or without 300 g steamed nopal. The glycemic index of nopal was 32.5±4, insulinemic index was 36.1±6, GIP index was 6.5±3.0, and GLP-1 index was 25.9±18. For those patients with type 2 diabetes who consumed the HCB+nopal, there was significantly lower area under the curve for glucose (287±30) than for those who consumed the HCB only (443±49), and lower incremental area under the curve for insulin (5,952±833 vs 7,313±1,090), and those patients with type 2 diabetes who consumed the HSPB avoided postprandial blood glucose peaks. Consumption of the HSPB+nopal significantly reduced the postprandial peaks of GIP concentration at 30 and 45 minutes and increased the antioxidant activity after 2 hours measured by the 2,2-diphenyl-1-picrilhidracyl method. These findings suggest that nopal could reduce postprandial blood glucose, serum insulin, and plasma GIP peaks, as well as increase antioxidant activity in healthy people and patients with type 2 diabetes.

Topics: Adult; Antioxidants; Breakfast; Diabetes Mellitus, Type 2; Female; Food, Preserved; Functional Food; Gastric Inhibitory Polypeptide; Glycemic Index; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Male; Medicine, Traditional; Mexico; Middle Aged; Opuntia; Plant Components, Aerial; Plant Proteins, Dietary; Postprandial Period; Soybean Proteins

Assess the pharmacodynamics of lixisenatide once daily (QD) versus liraglutide QD in type 2 diabetes insufficiently controlled on metformin.. In this 28-day, randomized, open-label, parallel-group, multicentre study (NCT01175473), patients (mean HbA1c 7.3%) received subcutaneous lixisenatide QD (10 µg weeks 1-2, then 20 µg; n = 77) or liraglutide QD (0.6 mg week 1, 1.2 mg week 2, then 1.8 mg; n = 71) 30 min before breakfast. Primary endpoint was change in postprandial plasma glucose (PPG) exposure from baseline to day 28 during a breakfast test meal.. Lixisenatide reduced PPG significantly more than liraglutide [mean change in AUC(0:30-4:30h) : -12.6 vs. -4.0 h·mmol/L, respectively; p < 0.0001 (0:30 h = start of meal)]. Change in maximum PPG excursion was -3.9 mmol/l vs. -1.4 mmol/l, respectively (p < 0.0001). More lixisenatide-treated patients achieved 2-h PPG <7.8 mmol/l (69% vs. 29%). Changes in fasting plasma glucose were greater with liraglutide (-0.3 vs. -1.3 mmol/l, p < 0.0001). Lixisenatide provided greater decreases in postprandial glucagon (p < 0.05), insulin (p < 0.0001) and C-peptide (p < 0.0001). Mean HbA1c decreased in both treatment groups (from 7.2% to 6.9% with lixisenatide vs. 7.4% to 6.9% with liraglutide) as did body weight (-1.6 kg vs. -2.4 kg, respectively). Overall incidence of adverse events was lower with lixisenatide (55%) versus liraglutide (65%), with no serious events or hypoglycaemia reported.. Once daily prebreakfast lixisenatide provided a significantly greater reduction in PPG (AUC) during a morning test meal versus prebreakfast liraglutide. Lixisenatide provided significant decreases in postprandial insulin, C-peptide (vs. an increase with liraglutide) and glucagon, and better gastrointestinal tolerability than liraglutide.

Topics: Adult; Aged; C-Peptide; Diabetes Mellitus, Type 2; Drug Administration Schedule; Drug Resistance; Female; Glucagon; Glucagon-Like Peptide 1; Glycated Hemoglobin; Humans; Hyperglycemia; Hyperinsulinism; Hypoglycemic Agents; Incretins; Injections, Subcutaneous; Liraglutide; Male; Metformin; Middle Aged; Peptides

Dairy proteins, in particular the whey fraction, exert insulinogenic properties and facilitate glycemic regulation through a mechanism involving elevation of certain plasma amino acids, and stimulation of incretins. Human milk is rich in whey protein and has not been investigated in this respect.. Nine healthy volunteers were served test meals consisting of human milk, bovine milk, reconstituted bovine whey- or casein protein in random order. All test meals contributed with 25 g intrinsic or added lactose, and a white wheat bread (WWB) meal was used as reference, providing 25 g starch. Post-prandial levels in plasma of glucose, insulin, incretins and amino acids were investigated at time intervals for up to 2 h.. All test meals elicited lower postprandial blood glucose responses, expressed as iAUC 0-120 min compared with the WWB (P < 0.05). The insulin response was increased following all test meals, although only significantly higher after whey. Plasma amino acids were correlated to insulin and incretin secretion (iAUC 0-60 min) (P ≤ 0.05). The lowered glycemia with the test meals (iAUC 0-90 min) was inversely correlated to GLP-1 (iAUC 0-30 min) (P ≤ 0.05).. This study shows that the glycemic response was significantly lower following all milk/milk protein based test meals, in comparison with WWB. The effect appears to originate from the protein fraction and early phase plasma amino acids and incretins were involved in the insulin secretion. Despite its lower protein content, the human milk was a potent GLP-1 secretagogue and showed insulinogenic properties similar to that seen with reconstituted bovine whey-protein, possibly due to the comparatively high proportion of whey in human milk.

Topics: Adult; Amino Acids; Animals; Breakfast; Caseins; Cattle; Cross-Over Studies; Female; Glucagon-Like Peptide 1; Glycemic Index; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Intestinal Mucosa; Male; Milk; Milk Proteins; Milk, Human; Pancreas; Pilot Projects; Whey Proteins; Young Adult

Diabetes is a chronic, progressive disease that calls for longitudinal data and analysis. We introduce a longitudinal mathematical model that is capable of representing the metabolic state of an individual at any point in time during their progression from normal glucose tolerance to type 2 diabetes (T2D) over a period of years. As an application of the model, we account for the diversity of pathways typically followed, focusing on two extreme alternatives, one that goes through impaired fasting glucose (IFG) first and one that goes through impaired glucose tolerance (IGT) first. These two pathways are widely recognized to stem from distinct metabolic abnormalities in hepatic glucose production and peripheral glucose uptake, respectively. We confirm this but go beyond to show that IFG and IGT lie on a continuum ranging from high hepatic insulin resistance and low peripheral insulin resistance to low hepatic resistance and high peripheral resistance. We show that IFG generally incurs IGT and IGT generally incurs IFG on the way to T2D, highlighting the difference between innate and acquired defects and the need to assess patients early to determine their underlying primary impairment and appropriately target therapy. We also consider other mechanisms, showing that IFG can result from impaired insulin secretion, that non-insulin-dependent glucose uptake can also mediate or interact with these pathways, and that impaired incretin signaling can accelerate T2D progression. We consider whether hyperinsulinemia can cause insulin resistance in addition to being a response to it and suggest that this is a minor effect.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Disease Progression; Fasting; Glucose; Glucose Intolerance; Glucose Tolerance Test; Humans; Hyperinsulinism; Incretins; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Liver; Models, Theoretical; Signal Transduction

The oral glucose test (OGT) is a useful tool for diagnosing insulin dysregulation (ID) and is somewhat repeatable in ponies under consistent management. This study aimed to determine whether the insulin and incretin responses to an OGT in ponies differed after short-term access to fertilised pasture, compared to unfertilised pasture, by using a randomised, repeated measures study design. Sixteen mixed-breed ponies were classified as severely insulin-dysregulated (SD; post-prandial insulin ≥80 μIU/mL) or not severely insulin-dysregulated (NSD; post-prandial insulin < 80 μIU/mL) using an OGT prior to the study. The ponies accessed pasture that was fertilised, or unfertilised, for 5 days (4 h/day, with supplemental hay provided at 0.7% bodyweight), with a 10 day period between phases. An OGT was performed after each phase. Glucose, insulin, active glucagon-like peptide-1 (aGLP-1), and glucose-dependent insulinotropic polypeptide (GIP) were measured in post-prandial blood samples.. The volume of fertilised pasture was five-fold greater than unfertilised pasture, with % non-structural carbohydrates (NSC) similar between all forages. Consuming fertilised pasture increased (P = 0.018) the serum insulin response to an OGT, compared to grazing unfertilised pasture. A limitation of the study was that pasture intake was unable to be quantified. Insulin responses were greater in SD, compared to NSD, ponies (P < 0.001) and remained well above the test cut-off at all times. A subset of ponies, initially screened as NSD, became (more) insulin-dysregulated after pasture access. Further, aGLP-1 was a significant predictor of insulin concentration in this cohort.. Whereas some insulin-dysregulated ponies were comparatively resistant to dietary intervention, others showed markedly different OGT responses following subtle changes in their forage-based diet. This implies that mild/early ID might be unmasked by dietary change, and that dietary management is important in these ponies. However, dietary management alone may not be adequate for all cases of ID.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Cross-Over Studies; Diet; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Metabolic Syndrome; Peptide Fragments; Queensland; Random Allocation

The influential role of incretin hormones on glucose metabolism in patients with a history of Roux-en-Y gastric bypass (RYGB) has been investigated thoroughly, but there has been little examination of the effect of incretins and ectopic lipids on altered glucose profiles, especially severe hypoglycemia in pregnant women with RYGB.. In this prospective clinical study, an oral glucose tolerance test (OGTT), an intravenous glucose tolerance test (IVGTT), and continuous glucose monitoring (CGM) were conducted in 25 women with RYGB during pregnancy, 19 of normal weight (NW) and 19 with obesity (OB) between the 24th and the 28th weeks of pregnancy, and 3 to 6 months post-partum. Post-partum, the ectopic lipid content in the liver, heart, and skeletal muscle was analyzed using. RYGB patients presented with major fluctuations in glucose profiles, including a high occurrence of postprandial hyperglycemic spikes and hypoglycemic events during the day, as well as a high risk of hypoglycemic periods during the night (2.9 ± 1.1% vs. 0.1 ± 0.2% in the OB and vs. 0.8 ± 0.6% in the NW groups, p < 0.001). During the extended OGTT, RYGB patients presented with exaggerated expression of GLP-1, which was the main driver of the exaggerated risk of postprandial hypoglycemia in a time-lagged correlation analysis. Basal and dynamic GLP-1 levels were not related to insulin sensitivity, insulin secretion, or beta cell function and did not differ between pregnant women with and without GDM. A lower amount of liver fat (2.34 ± 5.22% vs.5.68 ± 4.42%, p = 0.015), which was positively related to insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR: rho = 0.61, p = 0.002) and beta-cell function (insulinogenic index: rho = 0.65, p = 0.001), was observed in the RYGB group after delivery in comparison to the OB group.. GLP-1 is mainly involved in the regulation of postprandial glucose metabolism and therefore especially in the development of postprandial hypoglycemia in pregnant RYGB patients, who are characterized by major alterations in glucose profiles, and thus in long-term regulation, multiple organ-related mechanisms, such as the lipid content in the liver, must be involved.

Topics: Adult; Anastomosis, Roux-en-Y; Blood Glucose; Diabetes, Gestational; Female; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hyperglycemia; Hyperinsulinism; Incretins; Insulin Resistance; Insulin-Secreting Cells; Lipid Metabolism; Lipids; Obesity; Pregnancy

Supraphysiological insulin and incretin responses to a cereal-based diet have been described in horses and ponies with insulin dysregulation (ID). However, the hormonal responses to grazing have not yet been described.. To determine if there is a difference in the insulin and incretin responses to grazing pasture between insulin-dysregulated and healthy ponies.. A cohort of 16 ponies comprising 5 with normal insulin regulation (NIR), 6 with moderate ID (MID), and 5 with severe ID (SID).. In this case-control study, an oral glucose test (OGT) was used to determine the insulin responsiveness of each pony to PO carbohydrate before grazing pasture (4 hours) for 3 consecutive days. Serial blood samples collected during grazing were analyzed for glucose, insulin, glucose-dependent insulinotropic peptide (GIP) and active glucagon-like peptide-1 (aGLP-1), and compared among pony groups and day of pasture access.. The area under the insulin curve when grazing increased with ID severity (P < .03). The median (range) maximal insulin concentration was greater in the MID (72.5 [129] μIU/mL) and SID (255 [338.5] μIU/mL) groups, compared to the NIR (11.7 [24.9] μIU/mL) group (P < .03) and occurred within 2-4 hours of grazing. Postprandial OGT insulin concentration was positively correlated with 2 hours post-grazing insulin across all 3 grazing days (P ≤ .03). The aGLP-1 and GIP concentrations increased in response to grazing but did not differ among groups.. Grazing pasture provoked an increased insulin and incretin response in insulin-dysregulated ponies within 4 hours of grazing. The pasture and OGT insulin concentrations were correlated.

Topics: Animals; Blood Glucose; Case-Control Studies; Eating; Female; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose Tolerance Test; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Male

Compared with some other species, insulin dysregulation in equids is poorly understood. However, hyperinsulinemia causes laminitis, a significant and often lethal disease affecting the pedal bone/hoof wall attachment site. Until recently, hyperinsulinemia has been considered a counterregulatory response to insulin resistance (IR), but there is growing evidence to support a gastrointestinal etiology. Incretin hormones released from the proximal intestine, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, augment insulin secretion in several species but require investigation in horses. This study investigated peripheral and gut-derived factors impacting insulin secretion by comparing the response to intravenous (iv) and oral d-glucose. Oral and iv tests were performed in 22 ponies previously shown to be insulin dysregulated, of which only 15 were classified as IR (iv test). In a more detailed study, nine different ponies received four treatments: d-glucose orally, d-glucose iv, oats, and commercial grain mix. Insulin, glucose, and incretin concentrations were measured before and after each treatment. All nine ponies showed similar iv responses, but five were markedly hyperresponsive to oral d-glucose and four were not. Insulin responsiveness to oral d-glucose was strongly associated with blood glucose concentrations and oral glucose bioavailability, presumably driven by glucose absorption/distribution, as there was no difference in glucose clearance rates. Insulin was also positively associated with the active amide of GLP-1 following d-glucose and grain. This study has confirmed a functional enteroinsular axis in ponies that likely contributes to insulin dysregulation that may predispose them to laminitis. Moreover, iv tests for IR are not reliable predictors of the oral response to dietary nonstructural carbohydrate.

Topics: Animal Feed; Animals; Diet; Dietary Carbohydrates; Enteroendocrine Cells; Gastrointestinal Tract; Glucose Tolerance Test; Horse Diseases; Horses; Hyperinsulinism; Incretins; Insulin; Insulin Resistance

Dipeptidyl peptidase-4 (DPP-4) inhibitors increase circulating levels of incretin hormones, which can enhance insulin secretion and β cell function. The aim of this study was to evaluate the effectiveness of MK-626 (a novel DPP-4 inhibitor) to reduce the hyperglycemia and hyperinsulinemia of nonobese type 2 diabetic MKR mice. Twelve to 14-week-old hyperglycemic MKR mice were gavaged daily with MK-626 (3 mg/kg body weight) or vehicle (0.5% methyl cellulose (MC)) for 2 weeks. MK-626-treated mice displayed no change in body weight or adverse reactions, suggesting good tolerance of the drug. Fed blood glucose was significantly reduced over the 2-week experiment; however, it was also reduced in the MC group, suggesting an effect of gavage alone. Fed plasma insulin and glucagon levels and glucose tolerance of MK-626-treated mice were similar to those of MC mice. Therefore, treatment with MK-626 did not correct the prolonged hyperglycemia and impaired glucose tolerance of MKR mice.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dipeptidyl-Peptidase IV Inhibitors; Glucagon; Glucose; Glucose Intolerance; Homeostasis; Hyperglycemia; Hyperinsulinism; Incretins; Insulin; Insulin Secretion; Islets of Langerhans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Obese; Phenylalanine; Triazoles

We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene.. We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action.. Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p < 0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p < 0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p = 0.03) and GIP (p = 0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele had significantly reduced 24 h glucagon concentrations (p < 0.02) suggesting altered alpha cell function.. Elevated hepatic glucose production and reduced insulinotropic effect of incretin hormones contribute to an increased risk of type 2 diabetes in carriers of the rs7903146 risk T allele of TCF7L2.

Topics: Adolescent; Alleles; Blood Glucose; Diabetes Mellitus, Type 2; Genotype; Glucagon-Like Peptide 1; Glucose Clamp Technique; Glucose Tolerance Test; Glutaminase; Humans; Hyperinsulinism; Incretins; Insulin; Intracellular Signaling Peptides and Proteins; Liver; Male; Risk Factors; TCF Transcription Factors; Transcription Factor 7-Like 2 Protein; Tritium; Young Adult