Insulin Secretion In People Research Articles

Annual Prize Lecture 2024: Endogenous physiological mechanisms as basis for the treatment of obesity and type 2 diabetes.

In 1964, it was proven that postprandial insulin secretion is largely regulated by gut hormones and, in 1973, it was proposed that a gut hormone would also regulate appetite and food intake. Several gut hormones were tested for metabolic actions with disappointing results until the discovery of the proglucagon derivative, glucagon-like peptide-1 (GLP-1). This peptide from the distal intestine has preserved activity on insulin secretion in people with type 2 diabetes and turned out to regulate both secretion and motility in the gastrointestinal tract and importantly, appetite and food intake, thus functioning as an efficient 'ileal brake' hormone. However, the natural hormone acts predominantly via sensory afferent systems and is extremely rapidly removed from the circulation by enzymatic degradation and renal elimination, and increasing the doses merely results in nausea and vomiting. Lipidation of analogs turned out to provide both stability and limit renal elimination, and very slow up-titration of dosing improves tolerance. Indeed, the most recent agonists may near-normalize glycaemic control in type 2 diabetes, may cause weight losses of up to 25% of body weight, and significantly reduce cardiovascular risk, effects that resemble those of bariatric surgery. Thus, a solution to one of the most serious health problems of modern civilization, the increased morbidity and mortality of the metabolic syndrome, may be addressed by mobilization of one of the body's own regulatory mechanisms.

Adipose tissue–derived adipsin marks human aging in non-type 2 diabetes population

IntroductionAdipsin or complement factor D is an adipokine that augments insulin secretion, is altered in various degrees of obesity, and is involved in alternative complement pathway. However, whether adipsin has...

Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells

Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia.

342-OR: The Impact of Insulin Secretion and Insulin Sensitivity on Cognition in Adults with Prediabetes—The Diabetes Prevention Program Outcomes Study (DPPOS)

Dysglycemia is a significant risk factor for cognitive impairment. However, which pathophysiologic determinant of dysglycemia, impaired insulin sensitivity (ISens) or insulin secretion (ISecr), or both, contributes to poorer cognitive function is not established. Among 1,054 adults with prediabetes (PreD) from the DPPOS, who did not develop diabetes, we investigated the relationship between ISecr, ISens and cognitive function, hypothesizing that lower ISens and/or lower ISecr is associated with worse cognition. Early ISecr was estimated by the mean insulinogenic index (IGI; pmol/mmol) from repeated annual oral glucose tolerance tests and ISens was estimated by the mean 1/fasting insulin from repeated fasting blood draws. ISecr and ISens were calculated over approximately 12 years of follow-up. Verbal learning (Spanish-English Verbal Learning Test [SEVLT]) and processing speed (Digital Symbol Substitution Test [DSST]) were assessed at the end of the follow-up period. Separate linear regression models were run for each cognitive outcome. Models included both mean ISecr and mean ISens as the main predictor variables and were adjusted for demographic, lifestyle, cardiovascular factors, and medications. Contrary to our hypothesis and to prior studies, higher mean ISecr was associated with poorer performance on the DSST (-0.74 points per SD increase in IGI, 95% CI: -1.43, -0.05; p=0.03). Mean ISens was not associated with DSST, nor were mean ISecr or mean ISens associated with SEVLT. These results suggest that higher insulin secretion in people with longstanding PreD may negatively impact processing speed, a critical component of executive control. This relationship could reflect a compensatory response of insulin in people with worsening metabolic dysregulation, who may also have poorer cognition. Further study is needed to replicate these findings and to understand the role of insulin in cognitive function. Disclosure A. Shapiro: None. A.H. Tjaden: None. S. Edelstein: None. S.E. Kahn: Advisory Panel; Anji Pharmaceuticals, Bayer Inc., Boehringer Ingelheim Inc., Eli Lilly and Company, Merck & Co., Inc. Other Relationship; Novo Nordisk. P. Srikanthan: None. W.C. Knowler: None. E.M. Venditti: None. S. Golden: Advisory Panel; Abbott Diabetes, Medtronic. O. Carmichael: Research Support; Eli Lilly and Company. Advisory Panel; Novo Nordisk. Research Support; Nestlé Health Science. K.M. Gadde: Research Support; BioKier, Inc., National Institute of Diabetes and Digestive and Kidney Diseases. J.A. Luchsinger: Consultant; Merck KGaA. Other Relationship; Wolters Kluwer Health. D. Research Group: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UDK048489, UDK048339, UDK048377, UDK048349, UDK048381, UDK048468, UDK048434, UDK048485, UDK048375, UDK048514, UDK048437, UDK048413, UDK048411, UDK048406, UDK048380, UDK048397, UDK048412, UDK048404, UDK048387, UDK048407, UDK048443, UDK048400)

Liver-expressed antimicrobial peptide 2 is associated with improved pancreatic insulin secretion in adults with overweight and obesity.

To examine association of liver-expressed antimicrobial peptide 2 (LEAP2), an endogenous ghrelin antagonist with anorexiant effects, to key cardiometabolic risk factors in people with overweight and obesity. In this cross-sectional study, we sought to identify associations between LEAP2 levels and cardiometabolic risk factors, including body composition (dual X-ray absorptiometry), insulin and glucose metabolism (oral and intravenous glucose tolerance tests and hyperinsulinaemic-euglycaemic clamps), plasma lipids and inflammation markers (ELISA and multiplex assays). In 65 participants with overweight or obesity (63.1% male, mean age 31.3 ± 8.5 years), LEAP2 levels were associated with total body fat, but not with body mass index or waist-hip ratio in both univariable and age- and sex-adjusted models (P < 0.05). Higher LEAP2 level was also positively associated with higher insulin secretion in univariable (P=0.047) and multivariable models adjusted for age, sex and body fat (P=0.03), but not with fasting glucose levels (P ≥ 0.05). Higher LEAP2 levels were associated insulin resistance (P=0.07) after adjustment for age and sex, but the association disappeared after an additional adjustment for body fat (P=0.2). There was an inverse association between LEAP2 levels and nuclear factor kappa-B (NFκB) activity in the peripheral blood mononuclear cells in age-, sex- and body fat-adjusted models (P=0.04). There were no associations with cardiovascular risk factors (lipids, blood pressure) or other inflammation markers. These results provide important insights into the association between LEAP2 and cardiometabolic health in a high-risk population of individuals with overweight and obesity. This is a first report of an association between LEAP2 and insulin secretion, insulin sensitivity and NFκB activity. LEAP2 may represent an important potential therapeutic target to promote insulin secretion in people with type 2 diabetes and obesity.

Obesity Is Associated With Increased Basal and Postprandial β-Cell Insulin Secretion Even in the Absence of Insulin Resistance.

We tested the hypothesis that obesity, independent of insulin resistance, is associated with increased insulin secretion. We compared insulin kinetics before and after glucose ingestion in lean healthy people and people with obesity who were matched on multiorgan insulin sensitivity (inhibition of adipose tissue lipolysis and glucose production and stimulation of muscle glucose uptake) as assessed by using a two-stage hyperinsulinemic-euglycemic pancreatic clamp procedure in conjunction with glucose and palmitate tracer infusions and positron emission tomography. We also evaluated the effect of diet-induced weight loss on insulin secretion in people with obesity who did not improve insulin sensitivity despite marked (∼20%) weight loss. Basal and postprandial insulin secretion rates were >50% greater in people with obesity than lean people even though insulin sensitivity was not different between groups. Weight loss in people with obesity decreased insulin secretion by 35% even though insulin sensitivity did not change. These results demonstrate that increased insulin secretion in people with obesity is associated with excess adiposity itself and is not simply a compensatory response to insulin resistance. These findings have important implications regarding the pathogenesis of diabetes because hyperinsulinemia causes insulin resistance and insulin hypersecretion is an independent risk factor for developing diabetes.

Clinical and genetic characteristics of people with type1 diabetes who have discrepancies in titers of anti-glutamic acid decarboxylase antibody measured by radioimmunoassay and enzyme-linked immunosorbent assay.

Aims/IntroductionThe aim of the present study was to compare the clinical and genetic characteristics between people with type 1 diabetes who were positive and negative for autoantibodies against glutamic acid decarboxylase (GADA) measured by enzyme‐linked immunosorbent assay (ELISA) with low‐titer GADA measured by radioimmunoassay.Materials and MethodsAmong Japanese people with type 1 diabetes in whom GADA were measured by both ELISA and radioimmunoassay, those who had low titers of GADA measured by radioimmunoassay (1.5–10 U/mL), regardless of positivity for GADA measured by ELISA, were studied. There were 65 participants with acute‐onset type 1 diabetes and 30 participants with slowly progressive insulin‐dependent diabetes mellitus. Clinical characteristics and human leukocyte antigen types were compared in ELISA‐positive (≥5 U/mL) and ELISA‐negative participants. Endogenous insulin secretion was evaluated by C‐peptide index.ResultsAmong participants with slowly progressive insulin‐dependent diabetes mellitus, postprandial C‐peptide index was significantly higher in ELISA‐negative participants than in ELISA‐positive participants (r = 0.619, P = 0.002). Among 52 participants whose human leukocyte antigen typing was carried out, all of the participants with slowly progressive insulin‐dependent diabetes mellitus who had DRB1*09:01 were positive by GADA‐ELISA (P = 0.021). In acute‐onset type 1 diabetes participants, there were no significant differences for the C‐peptide index and human leukocyte antigen genotypes.ConclusionsThe difference in the positivity for GADA‐ELISA might reflect cytotoxicity toward pancreatic β‐cells and preservation of endogenous insulin secretion in people with slowly progressive insulin‐dependent diabetes mellitus. We also suggest that the difference in the GADA‐ELISA‐specific epitope depends on the human leukocyte antigen genotype.

Walking a fine line between β-cell secretion and proliferation

Of the many common genetic variants associated with type 2 diabetes, that in TCF7L2 remains the most studied because it has the greatest effect size. However, the mechanism by which this variant alters diabetes risk remains elusive. A new study adds another layer of complexity, suggesting that the effects of TCF7L2 are context-dependent, and highlights a novel interaction that might bias a β-cell to a secretory or proliferative phenotype. This in turn might open up new avenues to the restoration of insulin secretion in people with type 2 diabetes.

An update on the ‘gliptins’

Progressive impairment of insulin secretion in people with type 2 diabetes leads to blood glucose concentrations worsening over time, often resulting in escalation of blood glucose lowering therapy.1 In 2015/2016,...

Circulating adiponectin concentration is inversely associated with glucose tolerance and insulin secretion in people with newly diagnosed diabetes.

To examine the hypothesis that changes in serum adiponectin concentration inversely relate to changes in glucose tolerance and β-cell function already during the early stage of disease progression in recently diagnosed Type 1 and Type 2 diabetes mellitus. Participants in the prospective observational German Diabetes Study (Type 2 diabetes, n = 94; Type 1 diabetes, n = 42) underwent i.v. glucose tolerance and glucagon stimulation testing to assess pre-hepatic β-cell function, glucose tolerance index and C-peptide secretion within the first year of diabetes diagnosis and 2 years later. Associations of changes in serum concentrations of total adiponectin, high-molecular-weight adiponectin and their ratio with changes in the aforementioned metabolic variables were calculated using linear regression. Among people with Type 2 diabetes, 2-year increases in high-molecular-weight adiponectin and in high-molecular-weight/total adiponectin ratio were associated with decreases in glucose tolerance index of 0.1%/min (P = 0.020) and 0.8%/min (P = 0.013), respectively. Increases in high-molecular-weight/total adiponectin ratio were related to decreases in acute C-peptide secretion of 54.6% (P = 0.020). Among people with Type 1 diabetes, 2-year increases in total adiponectin were associated with 2-year decreases in acute C-peptide secretion of 56.2% (P = 0.035). Increases in adiponectin concentrations in the first 2 years after diagnosis were related to a worsening of acute insulin secretion and glucose tolerance index in Type 1 and Type 2 diabetes. (Clinical Trials Registry no.: NCT01055093).

Positive association of free triiodothyronine with pancreatic β-cell function in people with prediabetes.

To analyse the effects of thyroid hormones on β-cell function and glucose metabolism in people with prediabetes who are euthyroid. A total of 111 people who were euthyroid underwent 75-g oral glucose tolerance tests, of whom 52 were assigned to the normal glucose tolerance and 59 to the prediabetes groups. Homeostatic model assessment of β-cell function, insulinogenic index and areas under the curve for insulin and glucose were evaluated as indices of pancreatic β-cell function. In both groups, BMI, fasting insulin, homeostasis model assessment ratio and HDL cholesterol correlated significantly with all indices of pancreatic β-cell function. Free triiodothyronine correlated positively with all insulin secretion indices in the prediabetes group. Multiple linear regression analysis showed that free triiodothyronine was an independent variable that had a positive correlation with all indices of β-cell function in the prediabetes group. By contrast, no such correlation was found in the normal glucose tolerance group. Free triiodothyronine is associated with both basal and glucose-stimulated insulin secretion in people with prediabetes who are euthyroid; therefore, the regulation of insulin secretion by thyroid hormones is a potentially novel therapeutic target for the treatment of diabetes.

Similar weight‐adjusted insulin secretion and insulin sensitivity in short‐duration late autoimmune diabetes of adulthood (LADA) and Type 2 diabetes: Action LADA 8

To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with type 2 diabetes. A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year of insulin independency (group A) were age-matched pairwise to people with type 2 diabetes (group B) and to six people with type 2 diabetes of similar age and BMI (group C). β-Cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic-euglycemic clamp) and metabolic response during a mixed meal were studied. Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C) and could be explained by BMI alone in a multivariate analysis. Neither insulin pulsatility, incretin secretion nor insulin sensitivity differed among the groups. We found no evidence that LADA and type 2 diabetes were distinct disease entities beyond the differences explained by BMI.

Identification and Characterization of GLP-1 Receptor–Expressing Cells Using a New Transgenic Mouse Model

GLP-1 is an intestinal hormone with widespread actions on metabolism. Therapies based on GLP-1 are highly effective because they increase glucose-dependent insulin secretion in people with type 2 diabetes, but many reports suggest that GLP-1 has additional beneficial or, in some cases, potentially dangerous actions on other tissues, including the heart, vasculature, exocrine pancreas, liver, and central nervous system. Identifying which tissues express the GLP-1 receptor (GLP1R) is critical for the development of GLP-1-based therapies. Our objective was to use a method independent of GLP1R antibodies to identify and characterize the targets of GLP-1 in mice. Using newly generated glp1r-Cre mice crossed with fluorescent reporter strains, we show that major sites of glp1r expression include pancreatic β- and δ-cells, vascular smooth muscle, cardiac atrium, gastric antrum/pylorus, enteric neurones, and vagal and dorsal root ganglia. In the central nervous system, glp1r-fluorescent cells were abundant in the area postrema, arcuate nucleus, paraventricular nucleus, and ventromedial hypothalamus. Sporadic glp1r-fluorescent cells were found in pancreatic ducts. No glp1r-fluorescence was observed in ventricular cardiomyocytes. Enteric and vagal neurons positive for glp1r were activated by GLP-1 and may contribute to intestinal and central responses to locally released GLP-1, such as regulation of intestinal secretomotor activity and appetite.