Medicine (St Vincent's) - Theses

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Author: Vethakkan, Shireene Ratna × End date: 2010 × Start date: 2010 × Type: Doctorate ×

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    β-cell function, insulin sensitivity and non-esterified fatty acid (NEFA) dynamics after intra-portal allogeneic islet transplantation
    Vethakkan, Shireene Ratna ( 2010)
    BACKGROUND: Intra-portal allogeneic islet-transplantation is an effective means of biologic insulin-therapy in T1DM with debilitating hypoglycemia. While whole-pancreas-transplantation is known to restore normal biphasic, pulsatile insulin secretion and the incretin-response; little is known of islet-function and the metabolic milieu post-islet-transplantation. Few studies have compared recipients with T2DM subjects. AIMS: We aimed to evaluate Si pre- and post-transplantation as well as biphasic secretion, the incretin-response, glucose-sensitivity and NEFA suppression during an OGTT; comparing these results with controls and type 2 diabetics. METHODS: 3 islet-recipients in their 1st year of insulin-independence, 10 non-diabetic controls and 4 T2DM patients (requiring OHAs) each underwent 3 different glucose challenges on 3 separate days over 3-4 months, 4-6 weeks apart. The 3 procedures were a 4hr 75g-OGTT, an isoglycemic IVGTT and an FSIGT. Plasma glucose, insulin, C-peptide and NEFA were assayed. The islet-recipients underwent a non-insulin-modified FSIGT (enabling estimation of 2nd phase), the results of which were compared with historical controls similarly assessed. The rest underwent an insulin-modified-FSIGT. 2-step hyperinsulinemic-euglycemic-clamps were performed pre-transplantation and post-insulin-independence. RESULTS: Although recipients maintain an HbA1c ≤ 6% post-transplant without exogenous insulin, mean 2hr-glucose post-OGTT was 13 mmol/L. Clamp Si was unimpaired post-transplantation despite use of tacrolimus/mycophenolate. Post-transplantation, FSIGT second-phase secretion was restored to a greater extent than first (87% vs 46% normal). AIRg post-transplant was diminished compared with controls but ~8.5 times better than that in T2DM. During the OGTT while both early (0-30min) and late (30-240min) phase secretion were significantly and similarly reduced in recipients and T2DM compared with controls, more insulin was secreted per mmol glucose during late phase than early phase in recipients but not in type 2 diabetics. Islet-recipients had an oral DI ~26% of normal (4-fold higher thanT2DM). The incretin-response was reduced post-transplant and in T2DM (recipients 49%, T2DM 47%, controls 80%). Glucose-sensitivity was 26.3% of normal in recipients. NEFA suppression was unexpectedly normal and better than that in T2DM. Insulin secretion in recipients was worse during the OGTT (21% of normal) than the FSIGT (77% of normal). CONCLUSIONS: Our findings indicate that islet-recipients have a hybrid form of diabetes with features in common with T1DM (unimpaired Si) and T2DM (metabolic stability without exogenous insulin), and features unique to the post-transplant state (normal NEFA dynamics).Post-transplant diabetes is characterized by quantitative and qualitative β-cell secretory defects classically associated with the T2DM phenotype–reduced first-phase, incretin-response and glucose-sensitivity with preserved second-phase. Islet-recipients however have greater functional β-cell secretory-capacity and better insulin-sensitivity than OHA-requiring T2DM subjects. The presence of these secretory defects in recipients infused with healthy donor beta-cells indicate these are acquired functional β-cell defects common to all forms of dysglycemia resulting from a final common pathway of β-cell dysfunction/apoptosis. Despite these severe defects, insulin-independence is preserved - indicating that an oral DI 1/4th normal, in these highly insulin-sensitive subjects is sufficient for normoglycemia under free-living conditions. The impaired insulin response during the oral challenge compared with the intravenous challenge may be secondary to defects in incretin mechanisms and/or secretion of anti-incretin factors during the OGTT. Normal NEFA levels early post-transplant imply reduced risk of glucolipotoxicity and its deleterious effects on Si and graft-function. Our work highlights the important contribution of insulin-sensitivity and second-phase secretion towards maintaining normoglycemia post-transplant and hence the need to monitor these parameters. Abbreviations: type 1 diabetes (T1DM), type 2 diabetes (T2DM), oral hypoglycaemic agents (OHAs), oral glucose tolerance test (OGTT), isoglycemic intravenous glucose tolerance test (IVGTT), frequently-sampled intravenous glucose tolerance test (FSIGT), non-esterified fatty acids (NEFA), HbA1c (glycated hemoglobin), disposition index (DI), AIRg (acute insulin response to glucose), insulin-sensitivity (Si)