Acute-phase Insulin Secretion Research Articles

1160-P: Does Yoga Reduce the Risk of Conversion from Prediabetes to Diabetes by Improving Acute Phase Insulin Release? An Observation from an RCT

Background: Acute phase insulin secretion is disturbed in individuals with prediabetes. We have previously shown a significant risk reduction in 4,417 prediabetes individuals through Yoga. The present study explores yoga’s mechanism of action.Method: This randomized control trial included 42 (20 yoga;22 walkings;5 days/ week, 3Months) prediabetes (fasting glucose of 100 to 125 mg/dl) adults between 23 to 50 years. Serum Insulin and C peptide were assessed at 0, 3, 5, 7, 10, 15, 30,60and 90th minutes after 75grams of oral glucose. Pre-post assessments included fasting Glucose, HOMA%B(derived), GLP-1, free Triiodothyronine, perceived stress, and Heart rate variability.Results: There was a significant increase in the 10th minute (acute phase) Insulin and c-peptide levels in the yoga as compared to the control group. Improvement in GLP-1 and HOMA%B was significantly better in yoga than walking group. Yoga group also showed positive change in perceived stress and HRV. Simple linear regression of post data using acute phase Insulin as the dependent variable indicated a significant association between all measures(R2 = 0.806; p =<0.001).Conclusion: The shift to normoglycemia, due to an increase in acute phase insulin release, was associated with improved autonomic balance and reduced stress after yoga. More studies may confirm this unique first time observation.View largeDownload slideView largeDownload slide DisclosureR. Nagarathna: None. J. Kurian: None. V. Vijayakumar: None. H. R. Nagendra: None. R. N. Mavathur: None.FundingMinistry of AYUSH, Government of India (Z.28015-HPC (EMR)-AYUSH-B)

Impact of acute-phase insulin secretion on glycemic variability in insulin-treated patients with type 2 diabetes.

The association between β-cell function and glycemic variability remains to be clarified in insulin-treated patients with type 2 diabetes. Therefore, the study sought to examine the association of various indices of β-cell function with glycemic variability in Chinese insulin-treated patients with type 2 diabetes. Glycemic variability was assessed by the coefficient of variation (CV) of glucose levels with the use of continuous glucose monitoring (CGM). Basal β-cell function was evaluated by fasting C-peptide (FCP) and the homeostasis model assessment 2 for β-cell function (HOMA2-%β). Postload β-cell function was measured by 2-hour C-peptide (2hCP) and the acute C-peptide response (ACPR) to arginine. When a cutoff value of CV ≥ 36% was used to define unstable glucose, the multivariable-adjusted odds ratios for labile glycemic control were 0.34 (95% CI 0.18-0.64) for each 1 ng/mL increase in ACPR, 0.47 (95% CI 0.27-0.81) for each 1 ng/mL increase in FCP, 0.77 (95% CI 0.61-0.97) for each 1 ng/mL increase in 2hCP, and 1.00 (95% CI 0.98-1.01) for each 1% increase in HOMA2-%β. When we further adjusted for 2hCP and HOMA2-%β in the ACPR and FCP analyses, and adjusted for ACPR or FCP in the 2hCP analyses, only ACPR but not FCP or 2hPC remained to be a significant and inverse predictor for labile glycemic control. ACPR evaluated by the arginine stimulation test may be superior to other commonly used β-cell function parameters to reflect glycemic fluctuation in insulin-treated patients with type 2 diabetes.

β-Cell–Specific Protein Kinase A Activation Enhances the Efficiency of Glucose Control by Increasing Acute-Phase Insulin Secretion

Acute insulin secretion determines the efficiency of glucose clearance. Moreover, impaired acute insulin release is characteristic of reduced glucose control in the prediabetic state. Incretin hormones, which increase β-cell cAMP, restore acute-phase insulin secretion and improve glucose control. To determine the physiological role of the cAMP-dependent protein kinase (PKA), a mouse model was developed to increase PKA activity specifically in the pancreatic β-cells. In response to sustained hyperglycemia, PKA activity potentiated both acute and sustained insulin release. In contrast, a glucose bolus enhanced acute-phase insulin secretion alone. Acute-phase insulin secretion was increased 3.5-fold, reducing circulating glucose to 58% of levels in controls. Exendin-4 increased acute-phase insulin release to a similar degree as PKA activation. However, incretins did not augment the effects of PKA on acute-phase insulin secretion, consistent with incretins acting primarily via PKA to potentiate acute-phase insulin secretion. Intracellular calcium signaling was unaffected by PKA activation, suggesting that the effects of PKA on acute-phase insulin secretion are mediated by the phosphorylation of proteins involved in β-cell exocytosis. Thus, β-cell PKA activity transduces the cAMP signal to dramatically increase acute-phase insulin secretion, thereby enhancing the efficiency of insulin to control circulating glucose.

β-Cell-Specific Ablation of the Hepatocyte Growth Factor Receptor Results in Reduced Islet Size, Impaired Insulin Secretion, and Glucose Intolerance

Hepatocyte growth factor (HGF) and its c-met receptor consist of a paired signaling system that has been implicated in the regulation of pancreatic beta-cell survival, proliferation, and function. To define the role of HGF/c-met signaling in beta-cell biology in vivo, we have generated conditional knockout mice in which the c-met receptor gene was specifically inactivated in pancreatic beta cells by the Cre-loxP system. Mice with beta-cell-specific deletion of the c-met receptor (betamet-/-) displayed slight growth retardation, mild hyperglycemia, and decreased serum insulin levels at 6 months of age when compared with their control littermates. Deficiency of the c-met receptor in beta cells resulted in a complete loss of acute-phase insulin secretion in response to glucose and an impaired glucose tolerance. Glucose transporter-2 expression was down-regulated in the beta cells of betamet-/- mice. Compared to controls, betamet-/- mice exhibited reduced islet size and decreased insulin content in the pancreas, but displayed normal islet morphology. Therefore, HGF/c-met signaling plays an imperative role in controlling islet growth, in regulating beta-cell function, and in maintaining glucose homeostasis.

Fenofibrate, troglitazone, and 15-deoxy-Delta12,14-prostaglandin J2 close KATP channels and induce insulin secretion.

It is known that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands stimulate acute-phase insulin secretion with a rapid Ca2+ influx into pancreatic beta-cells, but the precise mechanisms are not clear. The effects of PPAR-alpha ligands on pancreatic beta-cells also remain unclear. We investigated the effects of PPAR-alpha ligands (fenofibrate and fenofibric acid), a PPAR-gamma ligand (troglitazone), and an endogenous ligand of PPAR-gamma [15-deoxy-Delta12,14-prostaglandin J2 (15-deoxy-Delta12,14-PGJ2)] on KATP channel activity in clonal hamster insulinoma cell line, HIT-T15 cells. As assessed by whole-cell patch clamp, fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 reduced the KATP channel currents, and inhibition continued after washout of these agents. The concentration-response curves of fenofibrate, fenofibric acid, troglitazone, and 15-deoxy-Delta12,14-PGJ2 showed half-maximal inhibition of KATP channel currents (IC50) at 3.26, 94, 2.1, and 7.3 micromol/l, respectively. Fenofibrate (> or = 10(-6) mol/l), 15-deoxy-Delta12,14-PGJ2 (> or = 5 x 10(-5) mol/l), and troglitazone (> or = 10(-6) mol/l) inhibited [3H]glibenclamide binding, but fenofibric acid did not. In addition, fenofibrate (> or = 10(-6) mol/l), fenofibric acid (10(-4) mol/l), troglitazone (10(-4) mol/l), and 15-deoxy-Delta12,14-PGJ2 (> or = 10(-5) mol/l) increased insulin secretion from HIT-T15 when applied for 10 min. Our data suggest that PPAR-alpha and -gamma ligands interact directly with the beta-cell membrane and stimulate insulin secretion.

Long-term association of cardiovascular risk factors with impaired insulin secretion and insulin resistance

The study aim was to investigate the association of cardiovascular risk factors with insulin resistance and impaired insulin secretion in an 8-year prospective population study in nondiabetic subjects. Cardiovascular risk factors of 271 subjects aged 16 to 61 years were measured at baseline, and insulin sensitivity and acute-phase insulin secretion were assessed by an intravenous glucose tolerance test (IVGTT) and Bergman's minimal model 8 years later. In logistic regression analysis, baseline high-density lipoprotein (HDL) and veryNlow-density lipoprotein (VLDL) cholesterol ( P < .001 and P = .006, respectively), total, low-density lipoprotein (LDL), and VLDL triglycerides ( P = .004, P = .048, and P = .002, respectively), apolipoprotein A1 ( P = .010), and uric acid ( P < .001) were associated with insulin resistance after adjustment for age and the body mass index (BMI). Systolic blood pressure ( P = .042) and VLDL cholesterol ( P = .018) were associated with impaired insulin secretion after adjustment for age and the BMI. This 8-year longitudinal study demonstrates that dyslipidemia, high blood pressure, and uric acid are associated with insulin resistance, whereas high systolic blood pressure and VLDL cholesterol are associated with impaired first-phase insulin secretion.

Evidence of islet cell autoimmunity in elderly patients with type 2 diabetes.

In light of an occurring growth of elderly people affected by type 2 diabetes and recent observations indicating that type 2 diabetes may be a disease of the innate immune system, we evaluated whether signs of islet cell autoimmunity are associated with an abnormal glucose control, the presence of insulin requirement, or an activation of the acute-phase response in older individuals with type 2 diabetes. GAD65 and IA-2 autoantibodies along with the acute-phase response markers fibrinogen and C-reactive protein were tested in 196 serum samples from patients with type 2 diabetes and in 94 nondiabetic control subjects over the age of 65 years from the Pittsburgh cohort of the Cardiovascular Health Study. Of the diabetic patients, 12% (24 of 196) had autoantibodies against GAD65 and/or IA-2, a prevalence significantly higher than that found in nondiabetic individuals (1 of 94, 1.1%; P = 0.001). Type 2 diabetic patients who were positive for GAD65 and/or IA-2 autoantibodies (Ab+), as compared with those negative for these autoantibodies (Ab-), had an abnormal oral glucose tolerance test (OGTT) (P = 0.03) before and a higher frequency of oral hypoglycemic treatment (P = 0.003) at the time of autoantibody testing. No differences were seen in the percentage of insulin requirement in the two groups. Moreover, a statistically significant increase in fibrinogen (P = 0.005) and C-reactive protein levels (P = 0.025) was found in type 2 diabetic patients with high levels of GAD65 and/or IA-2 autoantibodies as compared with Ab-patients and control subjects. In conclusion, in type 2 diabetic subjects > or =65 years old, the presence of islet cell autoimmunity is associated with an impairment of the acute-phase insulin secretion, as revealed by an OGTT. A pronounced activation of the acute-phase response, found to be associated with islet cell autoimmunity, may in part explain this defect in insulin secretion. These findings not only have direct implications for adequate classification and treatment of diabetes in the elderly, but also for understanding the autoimmune/inflammatory mechanisms involved in the pathogenesis of hyperglycemia.

Normal hepatic insulin sensitivity in lean, mild noninsulin-dependent diabetic patients.

We studied hepatic and extrahepatic insulin sensitivity and insulin release in seven nonobese patients with mild noninsulin-dependent diabetes mellitus (NIDDM) and 10 control subjects, matched for age, body mass index, and physical fitness. Glucose turnover was studied during sequential hyperinsulinemic euglycemic clamps (insulin infusion, 0.25 and 1.0 mU/kg BW.min), applying the hot-GINF (tracer-enriched glucose infusion) technique and using [6-3H]glucose. Hepatic glucose production was lower in hyperglycemic NIDDM patients during the basal period (P < 0.01), but was equivalent at similar glucose and insulin levels attained during both clamps. In contrast, during the low and high insulin clamps, glucose utilization was lower in NIDDM [14.90 +/- 1.00 vs. 17.24 +/- 0.83 (P < 0.01) and 41.37 +/- 3.05 vs. 50.54 +/- 3.61 mumol/kg BW.min (P < 0.01)]. Accordingly, the glucose infusion rate necessary to maintain euglycemia was lower in NIDDM [7.72 +/- 2.00 vs. 10.68 +/- 1.17 (P < 0.05) and 42.14 +/- 4.50 vs. 51.60 +/- 4.28 mumol/kg BW.min (P < 0.01)]. There was, however, a considerable overlap between patients and controls in the parameters describing insulin sensitivity. The insulin response to orally administered glucose as well as that to a standardized glucose infusion test (GIT) were diminished in NIDDM [average incremental insulin secretion during an oral glucose tolerance test, 88 +/- 28 vs. 251 +/- 50 pmol/L.min (P < 0.05); during first 10 min of GIT, 7 +/- 16 vs. 234 +/- 29 pmol/L.min (P < 0.001)]. There was no overlap in acute phase insulin secretion during the GIT between the groups. In conclusion, nonobese, mild NIDDM patients showed no impairment in hepatic, but a slight reduction in extrahepatic insulin sensitivity, with extensive overlap between diabetic and control subjects. In contrast, impairment of insulin release was very pronounced and without overlap.

The effect of endogenous gastric inhibitory polypeptide on glucose-induced insulin secretion in mild diabetes.

Diabetic subjects have previously been found to have increased secretion of immunoreactive gastric inhibitory polypeptide (IR-GIP) in response to oral glucose or triglyceride compared with normal subjects. In the present study, a group of 19 diabetics was selected with milder glucose intolerance (fasting plasma glucose = 109 mg. per deciliter) than those reported previously. In these diabetics no enhancement of IRGIP responses was found to either 75 gm. oral glucose or 50 ml. oral corn oil when compared with 13 subjects with normal carbohydrate tolerance. Some of the subjects were obese and, when assessed independently from glucose tolerance, obesity was associated with higher integrated IRGIP responses to oral glucose but not to oral corn oil. The degree of obesity (92 to 154 per cent ideal body weight) did not correlate with fasting or stimulated IRGIP responses of the 32 subjects. One hour after ingestion of 50 ml. corn oil, when IRGIP concentrations were maximal but glucose and insulin remained unaffected, the diabetic subjects showed increased relative acute-phase insulin secretion to a 20 gm. pulse of intravenous glucose compared with that from a glucose pulse alone (p &amp;lt; 0.01). Subjects with normal carbohydrate tolerance had no increase in relative acute insulin response to glucose after triglyceride priming. The relative second-phase insulin response (10 to 30 min.) increased significantly with triglyceride priming in both diabetics (p &amp;lt; 0.01) and nondiabetics (p &amp;lt; 0.05). Although glucose disappearance rates (Kg) correlated with relative insulin responses, the increase in insulin secretion with triglyceride priming was not associated with an increase in Kg. Although obese subjects show increased stimulated GIP responses to oral glucose, patients with mild diabetes have normal GIP secretion to oral glucose and to triglyceride, but show a GIP-associated increase in both phases of glucose-induced insulin secretion.

Inhibition of glucagon and insulin secretion by somatostatin in the rat pancreas perfused in situ.

Perfusion of growth hormone inhibitory factor (somatostatin) into rat pancreas inhibited secretion of glucagon and insulin into medium containing 5.5 mM glucose. A 15-min infusion of arginine (20 mM) greatly increased glucagon and insulin secretion. When perfused simultaneously with arginine, somatostatin (55 nM) abolished the increase in glucagon secretion. The acute phase of insulin secretion in response to arginine was attenuated by somatostatin, and subsequent secretion was decreased to control levels. Pretreatment for 5 min with somatostatin blocked even acute-phase insulin secretion in response to arginine. Somatostatin did not affect basal or glucose-stimulated secretion of insulin from rat pancreatic islets isolated by the collagenase technique. Arginine-stimulated secretion of insulin was enhanced by somatostatin in isolated islets. These results demonstrate a direct effect of somatostatin on the pancreas to inhibit secretion of glucagon and insulin. The failure of somatostatin to inhibit insulin secretion in pancreatic islets may be due to alterations in the beta cells produced by the isolation procedure. It is also possible that the effect of somatostatin on insulin secretion may be mediated indirectly.