Mechanisms of action of duodenal mucosal resurfacing in insulin resistant women with polycystic ovary syndrome.

BACKGROUND: Duodenal mucosal resurfacing (DMR) is a novel day-case endoscopic intervention which results in weight loss-independent reductions in HbA1c in patient with type 2 diabetes mellitus (T2DM). We hypothesized that DMR works by increasing insulin sensitivity and we aimed to investigate the mechanism of action of DMR through longitudinal metabolic phenotyping in humans. METHODS: Thirty-two insulin-resistant women with polycystic ovary syndrome (PCOS) and obesity were randomised in a double-blinded manner to DMR or sham endoscopy. They underwent measurements of insulin sensitivity using euglycaemic hyperinsulinaemic clamps, insulin secretion using oral glucose tolerance tests and reproductive function using weekly reproductive hormone profiles and ovarian ultrasonography for 6 months post-intervention. RESULTS: A small increase in total body insulin sensitivity measured by the clamp was observed in both groups at week 12. An increase in insulin sensitivity, as measured by HOMA-IR, was observed in both groups at week 24. There was an increase in the number of menses (median 2 DMR, 0.5 sham). There were no significant differences between the two groups in these outcomes or insulin secretion. CONCLUSIONS: These findings suggest that DMR does not work by increasing insulin sensitivity in euglycaemic, insulin resistant women with PCOS. The procedure may exert its effects only in the context of hyperglycaemia or pathologically hyperplastic, insulin-desensitised duodenal mucosa.

The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improvements in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODS: A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTS: Both groups exhibited enhancement in postprandial GLP-1 secretion and improvements in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONS: The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP-1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments.

Insulin clearance as the major player in the hyperinsulinaemia of black African men without diabetes.

AIM: To investigate relationships between insulin clearance, insulin secretion, hepatic fat accumulation and insulin sensitivity in black African (BA) and white European (WE) men. METHODS: Twenty-three BA and twenty-three WE men with normal glucose tolerance, matched for age and body mass index, underwent a hyperglycaemic clamp to measure insulin secretion and clearance, hyperinsulinaemic-euglycaemic clamp with stable glucose isotope infusion to measure whole-body and hepatic-specific insulin sensitivity, and magnetic resonance imaging to quantify intrahepatic lipid (IHL). RESULTS: BA men had higher glucose-stimulated peripheral insulin levels (48.1 [35.5, 65.2] × 103 vs. 29.9 [23.3, 38.4] × 103 pmol L-1 × min, P = .017) and lower endogeneous insulin clearance (771.6 [227.8] vs. 1381 [534.3] mL m-2 body surface area min -1 , P < .001) compared with WE men. There were no ethnic differences in beta-cell insulin secretion or beta-cell responsivity to glucose, even after adjustment for prevailing insulin sensitivity. In WE men, endogenous insulin clearance was correlated with whole-body insulin sensitivity (r = 0.691, P = .001) and inversely correlated with IHL (r = -0.674, P = .001). These associations were not found in BA men. CONCLUSIONS: While normally glucose-tolerant BA men have similar insulin secretory responses to their WE counterparts, they have markedly lower insulin clearance, which does not appear to be explained by either insulin resistance or hepatic fat accumulation. Low insulin clearance may be the primary mechanism of hyperinsulinaemia in populations of African origin.

Ethnic differences in intrahepatic lipid and its association with hepatic insulin sensitivity and insulin clearance between men of black and white ethnicity with early type 2 diabetes.

Intrahepatic lipid (IHL) is linked with reduced hepatic insulin sensitivity and insulin clearance. Despite their high risk for type 2 diabetes (T2D), there have been limited investigations of these relationships in black populations. We investigated these relationships in 18 white European (WE) and 18 black West African (BWA) men with T2D <5 years. They underwent magnetic resonance imaging to quantify IHL, a hyperinsulinemic euglycaemic clamp with [6,6 2 H2 ] glucose infusion to assess hepatic insulin sensitivity and a hyperglycaemic clamp to assess insulin clearance. BWA men had lower IHL than WE men (3.7 [5.3] vs 6.6 [10.6]%, P = 0.03). IHL was inversely associated with basal hepatic insulin sensitivity in WE but not BWA men (BWA: r = -0.01, P = 0.96; WE: r = -0.72, P = 0.006) with a significant interaction by ethnicity (Pinteraction = 0.05); however, IHL was not associated with % suppression of endogenous glucose production by insulin in either ethnicity. IHL showed a trend to an association with insulin clearance in BWA only (BWA: r = -0.42, P = 0.09; WE: r = -0.14, P = 0.58). The lack of association between IHL and hepatic insulin sensitivity in BWA men indicates IHL may play a lesser detrimental role in T2D in BWA men.