Renal Denervation Reverses Hepatic Insulin Resistance Induced by High-Fat Diet

Activation of the sympathetic nervous system (SNS) constitutes a putative mechanism of obesity-induced insulin resistance. Thus, we hypothesized that inhibiting the SNS by using renal denervation (RDN) will improve insulin sensitivity (S_I) in a nonhypertensive obese canine model. S_I was measured using euglycemic-hyperinsulinemic clamp (EGC), before (week 0 [w0]) and after 6 weeks of high-fat diet (w6-HFD) feeding and after either RDN (HFD + RDN) or sham surgery (HFD + sham). As expected, HFD induced insulin resistance in the liver (sham 2.5 ± 0.6 vs. 0.7 ± 0.6 x 10^–4 dL ⋅ kg^–1 ⋅ min^–1 ⋅ pmol/L^–1 at w0 vs. w6-HFD [P < 0.05], respectively; HFD + RDN 1.6 ± 0.3 vs. 0.5 ± 0.3 x 10^–4 dL ⋅ kg^–1 ⋅ min^–1 ⋅ pmol/L^–1 at w0 vs. w6-HFD [P < 0.001], respectively). In sham animals, this insulin resistance persisted, yet RDN completely normalized hepatic S_I in HFD-fed animals (1.8 ± 0.3 x 10^–4 dL ⋅ kg^–1 ⋅ min^–1 ⋅ pmol/L^–1 at HFD + RDN [P < 0.001] vs. w6-HFD, [P not significant] vs. w0) by reducing hepatic gluconeogenic genes, including G6Pase, PEPCK, and FOXO1. The data suggest that RDN downregulated hepatic gluconeogenesis primarily by upregulating liver X receptor α through the natriuretic peptide pathway. In conclusion, bilateral RDN completely normalizes hepatic S_I in obese canines. These preclinical data implicate a novel mechanistic role for the renal nerves in the regulation of insulin action specifically at the level of the liver and show that the renal nerves constitute a new therapeutic target to counteract insulin resistance.

Source Diabetes Pathophysiology http://ift.tt/2er8TUG

Metabolic Aberrations Impact Biophysical Integrity of Macromolecular Protein Pools in the Default Mode Network

The brain’s default mode network (DMN), having a high rate of basal energy metabolism, is vulnerable to altered glucose metabolism in type 2 diabetes mellitus (T2DM) due to insulin resistance and chronic hyperglycemia. Previous studies showed that functional connectivity and structural connectivity among the DMN nodal regions are compromised in T2DM. We applied magnetization transfer imaging to examine the impact of T2DM on the biophysical integrity of the DMN. The results showed that the biophysical integrity of macromolecular protein pools in the posterior cingulate cortex (PCC), a central DMN hub region, was selectively compromised in T2DM, whereas the other nodal regions of the DMN, including the medial prefrontal cortex, lateral inferior parietal cortex, precuneus, and medial and lateral temporal cortices, were biophysically intact compared with those of control subjects without diabetes. Furthermore, the degree of biophysical impairment of the PCC correlated with both hyperglycemia and vascular compromise, the two physiological hallmarks of diabetes. These new findings demonstrate that the PCC is vulnerable in the DMN and may shed light on the molecular neurobiology of T2DM and help to elucidate the pathophysiology of diabetes-related cognitive comorbidities and increased risk for dementia.

Source Diabetes Pathophysiology http://ift.tt/2eG0Lwc

Insulin Resistance Is Accompanied by Increased Fasting Glucagon and Delayed Glucagon Suppression in Individuals With Normal and Impaired Glucose Regulation

Hyperinsulinemia is an adaptive mechanism that enables the maintenance of normoglycemia in the presence of insulin resistance. We assessed whether glucagon is also involved in the adaptation to insulin resistance. A total of 1,437 individuals underwent an oral glucose tolerance test with measurements of circulating glucose, insulin, and glucagon concentrations at 0, 30 and 120 min. Early glucagon suppression was defined as suppression in the period from 0 to 30 min, and late glucagon suppression as 30 to 120 min after glucose intake. Insulin sensitivity was estimated by the validated insulin sensitivity index. Individuals with screen-detected diabetes had 30% higher fasting glucagon levels and diminished early glucagon suppression, but greater late glucagon suppression when compared with individuals with normal glucose tolerance (P ≤ 0.014). Higher insulin resistance was associated with higher fasting glucagon levels, less early glucagon suppression, and greater late glucagon suppression (P < 0.001). The relationship between insulin sensitivity and fasting glucagon concentrations was nonlinear (P < 0.001). In conclusion, increased fasting glucagon levels and delayed glucagon suppression, together with increased circulating insulin levels, develop in parallel with insulin resistance. Therefore, glucose maintenance during insulin resistance may depend not only on hyperinsulinemia but also on the ability to suppress glucagon early after glucose intake.

Source Diabetes Pathophysiology http://ift.tt/2er4iSn

F1F0 ATP Synthase-Cyclophilin D Interaction Contributes to Diabetes-Induced Synaptic Dysfunction and Cognitive Decline

Mitochondrial abnormalities are well known to cause cognitive decline. However, the underlying molecular basis of mitochondria-associated neuronal and synaptic dysfunction in the diabetic brain remains unclear. Here, using a mitochondrial single-channel patch clamp and cyclophilin D (CypD)-deficient mice (Ppif ^–/–) with streptozotocin-induced diabetes, we observed an increase in the probability of Ca²⁺-induced mitochondrial permeability transition pore (mPTP) opening in brain mitochondria of diabetic mice, which was further confirmed by mitochondrial swelling and cytochrome c release induced by Ca²⁺ overload. Diabetes-induced elevation of CypD triggers enhancement of F₁F₀ ATP synthase–CypD interaction, which in turn leads to mPTP opening. Indeed, in patients with diabetes, brain cypD protein levels were increased. Notably, blockade of the F₁F₀ ATP synthase–CypD interaction by CypD ablation protected against diabetes-induced mPTP opening, ATP synthesis deficits, oxidative stress, and mitochondria dysfunction. Furthermore, the absence of CypD alleviated deficits in synaptic plasticity, learning, and memory in diabetic mice. Thus, blockade of ATP synthase interaction with CypD provides a promising new target for therapeutic intervention in diabetic encephalopathy.

Source Diabetes Pathophysiology http://ift.tt/2eG2FwZ

Insulin-Like Growth Factor Axis and Gestational Diabetes Mellitus: A Longitudinal Study in a Multiracial Cohort

The insulin-like growth factor (IGF) axis may be implicated in glucose homeostasis, but its longitudinal profile across gestation in relation to the development of gestational diabetes mellitus (GDM) is largely unknown. We prospectively investigated IGF axis biomarkers in early-to-midpregnancy in relation to subsequent GDM risk in a case-control study of 107 case subjects with GDM and 214 control subjects without GDM, with blood sample collection at gestational weeks 10–14, 15–26, 23–31, and 33–39. Conditional logistic regression was used, adjusting for major risk factors including prepregnancy BMI. Plasma IGF-I and IGF binding protein 3 (IGFBP-3) concentrations and molar ratio of IGF-I to IGFBP-3 increased, whereas IGFBP-2 decreased throughout pregnancy. At gestational weeks 10–14, both IGF-I and IGF-I/IGFBP-3 were positively associated with GDM risk; adjusted odds ratio (OR) comparing the highest versus lowest quartile (OR_Q4-Q1) was 2.93 (95% CI 1.18, 7.30) for IGF-I and 3.31 (1.10, 9.98) for IGF-I/IGFBP-3. In contrast, higher IGFBP-2 levels were related to a substantially lower risk of GDM (OR_Q4-Q1 0.04 [0.01, 0.06]). Similar results were observed at gestational weeks 15–26. In sum, the IGF axis, IGFBP-2 in particular, may be implicated in the pathogenesis of GDM, with significant associations and incremental predictive value detected as early as gestational weeks 10–14, ~10–18 weeks earlier before GDM is typically screened for.

Source Diabetes Pathophysiology http://ift.tt/2er8Ec6