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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase-maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia-but not glycemia-was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.
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PMID:Iatrogenic Hyperinsulinemia, Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes as Revealed by Comparison With GCK-MODY (MODY2). 3109 78

All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed ('disallowed') in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1-7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell-beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion. Graphical abstract.
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PMID:Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity. 3289 9


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