Insulin signaling is required for insulin's direct and indirect action on hepatic glucose production

We and others have suggested that insulin predominantly acts indirectly to inhibit hepatic glucose production (HGP) via suppression of gluconeogenic precursors, FFAs, and glucagon. To test that hypothesis, we performed high-dose hyperinsulinemic-euglycemic clamps using [3-(3)H]-glucose in liver-specific insulin receptor knockout (LIRKO) mice, LIRKO mice treated with streptozotocin (LIRKO+STZ), and controls. In LIRKO mice, fasted glucose was normal, but insulin levels were elevated tenfold. STZ treatment reduced insulinemia by 60% with resulting hyperglycemia. Interestingly, basal HGP was similar in all three groups. During the clamp, HGP was suppressed by 82 +/- 17% in controls, but was not suppressed in either LIRKO or LIRKO+STZ mice. Glucose infusion and utilization were impaired ( approximately 50%) in LIRKO and LIRKO+STZ mice versus controls. Insulin suppressed FFAs similarly in all groups ( approximately 46%). Glucagon was not significantly suppressed during the clamp. Thus, in LIRKO mice, (a) high-dose insulin fails to suppress HGP indicating that both direct and indirect effects of insulin require an intact insulin-signaling pathway in the liver; (b) primary hepatic insulin resistance leads to hyperinsulinemia and secondary extrahepatic insulin resistance; and (c) lowering insulin levels with STZ tended to improve extrahepatic insulin sensitivity but failed to reveal the previously postulated indirect role of insulin in suppressing HGP.     

An application of upper-extremity constraint-induced movement therapy in a patient with subacute stroke.

BACKGROUND AND PURPOSE: The purpose of this case report is to demonstrate the application of constraint-induced movement therapy with an individual with upper-extremity hemiparesis within 4 months after sustaining a cerebrovascular accident (stroke). Such patients often fail to develop full potential use of their affected upper extremity, perhaps due to a "learned nonuse phenomenon." CASE DESCRIPTION: The patient was a 61-year-old woman with right-sided hemiparesis resulting from an ischemic lacunar infarct in the posterior limb of the left internal capsule. The patient's less-involved hand was constrained in a mitten so that she could not use the hand during waking hours, except for bathing and toileting. On each weekday of the 14-day intervention period, the patient spent 6 hours being supervised while performing tasks using the paretic upper extremity. Pretreatment, posttreatment, and 3-month follow-up outcome measures included the Wolf Motor Function Test and the Motor Activity Log (MAL). OUTCOMES: For the Wolf Motor Function Test, both the mean and median times to complete 16 tasks improved from pretreatment to posttreatment and from posttreatment to follow-up. Results of the MAL indicated an improved self-report of both "how well" and "how much" the patient used her affected limb in 30 specified daily tasks. These improvements persisted to the follow-up. DISCUSSION: Two weeks of constraining the unaffected limb, coupled with practice of functional movements of the impaired limb, may be an effective method for restoring motor function within a few months after cerebral insult. Encouraging improvements such as these strongly suggest the need for a group design that would explore this type of intervention in more detail.     

In the Eye of the Storm: Bioethics in the Time of COVID-19

HSS Journal ® -     

Holmium laser enucleation of the prostate in Jehovah’s Witness patients

Purpose

To evaluate if HoLEP is a viable option for male patients with medication-refractory urinary symptoms due to an enlarged prostate who are surgical candidates, but do not accept blood product transfusion.

Materials and methods

Between August 2008 and March 2019, nine Jehovah’s Witness patients were undergoing HoLEP for relief of lower urinary tract symptoms and urinary retention. We described change in hemoglobin, change in PSA, enucleated prostate weight, enucleation and morcellation times, length of stay, and postoperative retention rate.

Results

The average age was 71.4 years (range 53–87). Urinary retention requiring catheterization was present in seven patients (78%). Two patients had a known diagnosis of prostate cancer preoperatively. The mean preoperative PSA on average was 21.6 ng/dL. Patients had a wide range of gland sizes, with a mean enucleated weight of 141 g (range 18–344 g). Mean reduction in hemoglobin was 16.9% following HoLEP. All patients managed to void postoperatively. All but one patient went home on postoperative day 1, and this patient went home on postoperative day 2. No patients required blood product transfusion or return to the operating room for clot irrigation postoperatively.

Conclusion

HoLEP is a reasonable option for Jehovah’s Witness and other patients with contraindications to blood product transfusion requiring surgical management of urinary symptoms due to enlarged prostate.

     

Telomeres, stem cells, senescence, and cancer

Mammalian aging occurs in part because of a decline in the restorative capacity of tissue stem cells. These self-renewing cells are rendered malignant by a small number of oncogenic mutations, and overlapping tumor suppressor mechanisms (e.g., p16(INK4a)-Rb, ARF-p53, and the telomere) have evolved to ward against this possibility. These beneficial antitumor pathways, however, appear also to limit the stem cell life span, thereby contributing to aging.