Insulin enhances renal glucose excretion: relation to insulin sensitivity and sodium-glucose cotransport.

INTRODUCTION: Insulin regulates renal glucose production and utilization; both these fluxes are increased in type 2 diabetes (T2D). Whether insulin also controls urinary glucose excretion is not known. METHODS: We applied the pancreatic clamp technique in 12 healthy subjects and 13 T2D subjects. Each participant received a somatostatin infusion and a variable glucose infusion to achieve (within 1 hour) and maintain glycemia at 22 mmol/L for 3 hours; next, a constant insulin infusion (240 pmol/min/kg) was added for another 3 hours. Urine was collected separately in each period for glucose and creatinine determination. RESULTS: During saline, glucose excretion was lower in T2D than controls in absolute terms (0.49 (0.32) vs 0.69 (0.18) mmol/min, median (IQR), p=0.01) and as a fraction of filtered glucose (16.2 (6.4) vs 19.9 (7.5)%, p<0.001). With insulin, whole-body glucose disposal rose more in controls than T2D (183 (48) vs 101 (48) µmol/kgFFM/min, p<0.0003). Insulin stimulated absolute and fractional glucose excretion in controls (p<0.01) but not in T2D. Sodium excretion paralleled glucose excretion. In the pooled data, fractional glucose excretion was directly related to whole-body glucose disposal and to fractional sodium excretion (r=0.52 and 0.54, both p<0.01). In another group of healthy controls, empagliflozin was administered before starting the pancreatic clamp to block sodium-glucose cotransporter 2 (SGLT2). Under these conditions, insulin still enhanced both glucose and sodium excretion. CONCLUSIONS: Acute exogenous insulin infusion jointly stimulates renal glucose and sodium excretion, indicating that the effect may be mediated by SGLTs. This action is resistant in patients with diabetes, accounting for their increased retention of glucose and sodium, and is not abolished by partial SGLT2 inhibition by empagliflozin.

Effects of acute NEFA manipulation on incretin-induced insulin secretion in participants with and without type 2 diabetes.

AIMS/HYPOTHESIS: Incretin effect-the potentiation of glucose-stimulated insulin release induced by the oral vs the i.v. route-is impaired in dysglycaemic states. Despite evidence from human islet studies that NEFA interfere with incretin function, little information is available about the effect in humans. We tested the impact of acute bidirectional NEFA manipulation on the incretin effect in humans. METHODS: Thirteen individuals with type 2 diabetes and ten non-diabetic volunteers had a 3 h OGTT, and, a week later, an i.v. isoglycaemic glucose infusion (ISO; OGTT matched). Both pairs of studies were repeated during an exogenous lipid infusion in the non-diabetic volunteers, and following acipimox administration (to inhibit lipolysis) in people with diabetes. Mathematical modelling of insulin secretion dynamics assessed total insulin secretion (TIS), beta cell glucose sensitivity (ß-GS), glucose-induced potentiation (PGLU) and incretin-induced potentiation (PINCR); the oral glucose sensitivity index was used to estimate insulin sensitivity. RESULTS: Lipid infusion increased TIS (from 61 [interquartile range 26] to 78 [31] nmol/m2 on OGTT and from 29 nmol/m2 [26] to 57 nmol/m2 [30] on ISO) and induced insulin resistance. PINCR decreased from 1.6 [1.1] to 1.3 [0.1] (p < 0.05). ß-GS, PGLU and glucagon, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) responses were unaffected. Acipimox (lowering NEFA by ~55%) reduced plasma glucose and TIS and enhanced insulin sensitivity, but did not change ß-GS, PINCR, PGLU or glucagon, GLP-1 or GIP responses. As the per cent difference, incretin effect was decreased in non-diabetic participants and unchanged in those with diabetes. CONCLUSIONS/INTERPRETATION: Raising NEFA selectively impairs incretin effect and insulin sensitivity in non-diabetic individuals, while acute NEFA reduction lowers plasma glucose and enhances insulin sensitivity in people with diabetes but does not correct the impaired incretin-induced potentiation.

Subclinical hypothyroidism increases the risk for depression in the elderly.

In order to determine if subclinical hypothyroidism is a risk factor for depression in the elderly, a total of 323 individuals over 60 years old were interviewed using the Structured Clinical Interview for Diagnosis and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) for mood disturbances. Patients were divided into Group I: 252 patients (184 females, 68 males; median age: 67 years, range: 60-89 years) with elevated serum thyrotropin (TSH) levels and Group II: 71 patients (45 females, 26 males; median age: 67 years, range: 60-92 years) with diagnosis of depression. Serum TSH and free thyroxine (fT4) were measured by sensitive assays. Thyroid antibodies were determined by IRMA. Depression was observed in 24 (9.5%) Group I patients and was frequent in subclinical hypothyroidism patients (14/24 = 58.3%). On the other hand, elevated TSH levels were found in 22 (30.9%) Group II patients. Depression was observed more frequently among individuals with subclinical (74/149 = 49.7%) hypothyroidism than among individuals with overt hypothyroidism (21/125 = 16.8%) (p < 0.001). Indeed, subclinical hypothyroidism increased the risk for a patient to present depression more than four times (OR = 4.886; 95% confidence interval = 2.768-8.627). Our results demonstrate that subclinical hypothyroidism increases the risk for depression and emphasize the importance of thyroid screening tests in the elderly.