Insulin enhances glucose-stimulated insulin secretion in healthy humans

Abstract

Islet β-cells express both insulin receptors and insulin-signaling proteins. Recent evidence from rodents in vivo and from islets isolated from rodents or humans suggests that the insulin signaling pathway is physiologically important for glucose sensing. We evaluated whether insulin regulates β-cell function in healthy humans in vivo. Glucose-induced insulin secretion was assessed in healthy humans following 4-h saline (low insulin/sham clamp) or isoglycemic-hyperinsulinemic (high insulin) clamps using B28-Asp insulin that could be immunologically distinguished from endogenous insulin. Insulin and C-peptide clearance were evaluated to understand the impact of hyperinsulinemia on estimates of β-cell function. Preexposure to exogenous insulin increased the endogenous insulin secretory response to glucose by ≈40%. C-peptide response also increased, although not to the level predicted by insulin. Insulin clearance was not saturated at hyperinsulinemia, but metabolic clearance of C-peptide, assessed by infusion of stable isotope-labeled C-peptide, increased modestly during hyperinsulinemic clamp. These studies demonstrate that insulin potentiates glucose-stimulated insulin secretion in vivo in healthy humans. In addition, hyperinsulinemia increases C-peptide clearance, which may lead to modest underestimation of β-cell secretory response when using these methods during prolonged dynamic testing. beta cell | type 2 diabetes mellitus | insulin resistance | insulin clearance |

Determinants of reversibility of β-cell dysfunction in response to short-term intensive insulin therapy in patients with early type 2 diabetes

“…These apparent beneficial effects of insulin, compared with oral medications, suggest that the relevant mechanisms underlying long-term improvement in ␤-cell function likely extend beyond glucose lowering alone. This concept is further supported by studies showing that preceding exposure to exogenous insulin can enhance glucose-stimulated insulin secretion in healthy individuals (2,19). Coupled with evidence that islet cells express insulin receptors and signaling proteins whose disruption can lead to defective glucose metabolism in animal models (8,16), these data support an important physiological role for insulin signaling in the ␤-cell, which may potentially be relevant to the improvement in ␤-cell function that can be achieved with early short-term IIT.…”

“…As shown in Fig. 1, the study population had tight glycemic control while receiving IIT (e.g., mean 2-h postprandial capillary glucose levels in week 1 were Ͻ8.0 mmol/l and still improved further in weeks [2][3][4]. Despite this tight glycemic control, participants had very low rates of any hypoglycemia, even with the very liberal definition (blood glucose Յ3.9 mmol/l) used in this study.…”

Ameliorated pancreatic β cell dysfunction in type 2 diabetic patients treated with a sodium-glucose cotransporter 2 inhibitor ipragliflozin

“…On the other hand, the protein catabolism in skeletal muscle, leading to the decrease of muscle mass, would be reflected by reduced serum creatinine levels. The reduction of serum creatinine levels might be masked at 4 weeks by cemia-independent action on β cells via these pathways [29], although exogenous administration of physiological-dose insulin in vivo may have a limited if any influence on local insulin concentration around β cells. In contrast, SGLT2 inhibitors, a new class of anti-diabetic agents, lack a direct action on the β cell; they lower glucose levels by enhancing urinary glucose excretion [5].…”

Nephrin Contributes to Insulin Secretion and Affects Mammalian Target of Rapamycin Signaling Independently of Insulin Receptor

“…Interestingly, NP deficiency in podocytes leads to the impairment of insulin-stimulated glucose uptake, 32 suggesting that NP may positively affect raft-dependent insulin signaling. 33 In the pancreas, autocrine insulin signaling through insulin receptor A (IRA) leads to p70S6K-dependent insulin transcription, whereas insulin signaling through IRB augments Akt-dependent glucokinase transcription, 34 thus facilitating pancreatic b-cell function in humans 35 and rodents. 36 NP expression has been described in both mouse and human pancreas, 37,38 where NP regulates glucose-stimulated insulin release (GSIR) through Y1176 and Y1193 phosphorylation.…”