Demonstration of Glycated Insulin in Human Diabetic Plasma and Decreased Biological Activity Assessed by Euglycemic-Hyperinsulinemic Clamp Technique in Humans

Abstract

. Measurement of glycated insulin in plasma of type 2 diabetic subjects by specific RIA gave circulating levels of 10.1 ؎ 2.3 pmol/l, corresponding to ϳ9% total insulin. Biological activity of pure synthetic monoglycated insulin (insulin B-chain Phe 1 -glucitol adduct) was evaluated in seven overnight-fasted healthy nonobese male volunteers using two-step euglycemichyperinsulinemic clamps (2 h at 16.6 g ⅐ kg ؊1 ⅐ min ؊1 , followed by 2 h at 83.0 g ⅐ kg ؊1 ⅐ min ؊1 ; corresponding to 0.4 and 2.0 mU ⅐ kg ؊1 ⅐ min ؊1 ). At the lower dose, the exogenous glucose infusion rates required to maintain euglycemia during steady state were significantly lower with glycated insulin (P < 0.01) and ϳ70% more glycated insulin was required to induce a similar rate of insulin-mediated glucose uptake. Maximal responses at the higher rates of infusion were similar for glycated and control insulin. Inhibitory effects on endogenous glucose production, insulin secretion, and lipolysis, as indicated by measurements of C-peptide, nonesterified free fatty acids, and glycerol, were also similar. Receptor binding to CHO-T cells transfected with human insulin receptor and in vivo metabolic clearance revealed no differences between glycated and native insulin, suggesting that impaired biological activity is due to a postreceptor effect. The present demonstration of glycated insulin in human plasma and related impairment of physiological insulin-mediated glucose uptake suggests a role for glycated insulin in glucose toxicity and impaired insulin action in type 2 diabetes. Diabetes 52:492-498, 2003

Terminalia belliricastimulates the secretion and action of insulin and inhibits starch digestion and protein glycationin vitro

“…It is also potentially interesting that insulin is normally glycated in vivo and that glycated insulin has reduced biological activity (24,25) . This raises the possibility that inhibition of protein glycation may have benefits in addition to serving as a prophylactic for diabetic complications.…”

Demonstration of increased concentrations of circulating glycated insulin in human Type 2 diabetes using a novel and specific radioimmunoassay

“…Evidence includes the demonstration of increased concentrations of glycated insulin in the pancreas of various animal models of diabetes [1,8,9] and the time-and concentration-dependent glycation of insulin in both isolated mouse islets or clonal insulin secreting cell lines under hyperglycaemic conditions [1,2]. We have previously shown the impaired biological activity of glycated insulin using in vitro studies with isolated muscle preparations and in vivo studies using animal models or healthy human subjects subjected to hyperinsulinaemic euglycaemic glucose clamps [3,4,5,6].…”

“…Previous studies have shown that glycated insulin has a reduced ability to regulate plasma glucose homeostasis in vivo and to stimulate adipose tissue lipogenesis or glucose uptake and oxidation by isolated diaphragm and abdominal muscle in vitro [3,4,5]. Studies in healthy human volunteers using the hyperinsulinaemic-euglycaemic glucose clamp technique suggest that glycated insulin could contribute to insulin resistance in Type 2 diabetes mellitus [6].…”

“…Previous studies have shown that glycated insulin has a reduced ability to regulate plasma glucose homeostasis in vivo and to stimulate adipose tissue lipogenesis or glucose uptake and oxidation by isolated diaphragm and abdominal muscle in vitro [3,4,5]. Studies in healthy human volunteers using the hyperinsulinaemic-euglycaemic glucose clamp technique suggest that glycated insulin could contribute to insulin resistance in Type 2 diabetes mellitus [6].The site of glycation of human insulin has now been identified by electrospray tandem mass spectrometry as the N-terminal Phe 1 of the B-chain [7], enabling the development of a sensitive and specific radioimmunoassay to measure concentrations of glycated insulin and to identify glycated insulin in pancreatic islets using immunohistochemistry [8]. High performance liquid chromatography techniques used previously were neither sensitive nor reliable Formation of advanced glycation-end products (AGEs) plays an important role in long-term metabolic consequences of diabetes including ophthalmic, renal and atherosclerotic vascular complications.…”

Determining the relationship between dietary carbohydrate intake and insulin resistance

“…The dynamic relationship between insulin resistance and b-cell function can be seriously impaired by chronic hyperglycaemia through 'glucotoxicity' (Yki-Jarvinen, 1992) which can exacerbate both fundamental defects, aggregated by environmental factors superimposed on genetic predisposition to insulin resistance and type 2 diabetes. Under conditions of glucotoxicity, insulin is glycated in the pancreatic b-cell and may be released into the circulation in this form (Abdel-Wahab et al 1996;Hunter et al 2003). Glycated proteins including HbA 1c and insulin do not have the same properties as parental molecules; in the case of glycated insulin, this glycated form is likely to contribute to the progressive deterioration of glucose tolerance in diabetes (Hunter et al 2003;Kaiser et al 2003).…”