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      Metabolic Contrasts Between Youth and Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes: I. Observations Using the Hyperglycemic Clamp

      research-article
      The RISE Consortium *
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      Diabetes Care
      American Diabetes Association

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          Abstract

          OBJECTIVE

          To compare insulin sensitivity (M/I) and β-cell responses in youth versus adults with impaired glucose tolerance (IGT) or drug-naïve, recently diagnosed type 2 diabetes.

          RESEARCH DESIGN AND METHODS

          In 66 youth (80.3% with IGT) and 355 adults (70.7% IGT), hyperglycemic clamps were used to measure 1) M/I, 2) acute (0–10 min [first phase]) C-peptide (ACPR g) and insulin (AIR g) responses to glucose, 3) steady-state C-peptide and insulin concentrations at plasma glucose of 11.1 mmol/L, and 4) arginine-stimulated maximum C-peptide (ACPR max) and insulin (AIR max) responses at plasma glucose >25 mmol/L. The fasting C-peptide–to–insulin ratio was used as an estimate of insulin clearance.

          RESULTS

          Insulin sensitivity was 46% lower in youth compared with adults ( P < 0.001), and youth had greater acute and steady-state C-peptide (2.3- and 1.3-fold, respectively; each P < 0.001) and insulin responses to glucose (AIR g 3.0-fold and steady state 2.2-fold; each P < 0.001). Arginine-stimulated C-peptide and insulin responses were also greater in youth (1.6- and 1.7-fold, respectively; each P < 0.001). After adjustment for insulin sensitivity, all β-cell responses remained significantly greater in youth. Insulin clearance was reduced in youth ( P < 0.001). Participants with diabetes had greater insulin sensitivity ( P = 0.026), with lesser C-peptide and insulin responses than those with IGT (all P < 0.001) but similar insulin clearance ( P = 0.109).

          CONCLUSIONS

          In people with IGT or recently diagnosed diabetes, youth have lower insulin sensitivity, hyperresponsive β-cells, and reduced insulin clearance compared with adults. Whether these age-related differences contribute to declining β-cell function and/or impact responses to glucose-lowering interventions remains to be determined.

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          Most cited references21

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          IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040.

          To produce current estimates of the national, regional and global impact of diabetes for 2015 and 2040.
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            Glucose clamp technique: a method for quantifying insulin secretion and resistance.

            Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.
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              Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women.

              Type 2 diabetes frequently results from progressive failure of pancreatic beta-cell function in the presence of chronic insulin resistance. We tested whether chronic amelioration of insulin resistance would preserve pancreatic beta-cell function and delay or prevent the onset of type 2 diabetes in high-risk Hispanic women. Women with previous gestational diabetes were randomized to placebo (n = 133) or the insulin-sensitizing drug troglitazone (400 mg/day; n = 133) administered in double-blind fashion. Fasting plasma glucose was measured every 3 months, and oral glucose tolerance tests (OGTTs) were performed annually to detect diabetes. Intravenous glucose tolerance tests (IVGTTs) were performed at baseline and 3 months later to identify early metabolic changes associated with any protection from diabetes. Women who did not develop diabetes during the trial returned for OGTTs and IVGTTs 8 months after study medications were stopped. During a median follow-up of 30 months on blinded medication, average annual diabetes incidence rates in the 236 women who returned for at least one follow-up visit were 12.1 and 5.4% in women assigned to placebo and troglitazone, respectively (P < 0.01). Protection from diabetes in the troglitazone group 1) was closely related to the degree of reduction in endogenous insulin requirements 3 months after randomization, 2) persisted 8 months after study medications were stopped, and 3) was associated with preservation of beta-cell compensation for insulin resistance. Treatment with troglitazone delayed or prevented the onset of type 2 diabetes in high-risk Hispanic women. The protective effect was associated with the preservation of pancreatic beta-cell function and appeared to be mediated by a reduction in the secretory demands placed on beta-cells by chronic insulin resistance.
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                Author and article information

                Journal
                Diabetes Care
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                August 2018
                25 June 2018
                : 41
                : 8
                : 1696-1706
                Affiliations
                [1]RISE Coordinating Center, Rockville, MD
                Author notes
                Corresponding author: Sharon L. Edelstein, rise@ 123456bsc.gwu.edu .
                Article
                0244
                10.2337/dc18-0244
                6054493
                29941497
                54ad974e-ad87-4807-bacf-252d037ea21f
                © 2018 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

                History
                : 31 January 2018
                : 28 April 2018
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 30, Pages: 11
                Funding
                Funded by: NIDDK, DOI http://dx.doi.org/10.13039/100000062;
                Award ID: U01-DK-094406
                Award ID: U01-DK-094430
                Award ID: U01-DK-094431
                Award ID: U01-DK-094438
                Award ID: U01-DK-094467
                Categories
                0702
                1033
                Pathophysiology/Complications

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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