Renal compensation for impaired hepatic glucose release during hypoglycemia in type 2 diabetes: further evidence for hepatorenal reciprocity.

During liver transplantation and after both meal ingestion and prolonged fasting, renal glucose release (RGR) increases while hepatic glucose release (HGR) decreases. These and other observations have led to the concept of hepatorenal reciprocity. According to this concept, reciprocal changes in hepatic and renal glucose release may occur to minimize deviations from normal glucose homeostasis. We further assessed this concept by testing the hypothesis that during counterregulation of hypoglycemia in patients with type 2 diabetes, who would be expected to have reduced HGR, RGR would be increased. Accordingly, we performed hypoglycemic hyperinsulinemic clamp experiments (approximately 3.1 mmol/l) in 12 type 2 diabetic and in 10 age-weight-matched nondiabetic volunteers and measured total endogenous glucose release (TEGR) and RGR using a combined isotopic net balance approach. HGR was calculated as the difference between TEGR and RGR since only these organs are capable of releasing glucose. We found that during comparable hypoglycemia and hyperinsulinemia, TEGR was reduced in type 2 diabetes (6.6 +/- 0.6 vs. 10.2 +/- 1.1 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.01) due to reduced HGR (3.9 +/- 0.5 vs. 8.6 +/- 1.0 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.0015). In contrast, RGR was increased approximately twofold in type 2 diabetes (3.3 +/- 0.5 vs. 1.6 +/- 0.3 micromol. kg(-1). min(-1) in nondiabetic volunteers, P = 0.015). Plasma epinephrine, lactate, and free fatty acid concentrations, which would promote RGR, were also greater in type 2 diabetes (all P < 0.01). Our results provide further support for hepatorenal reciprocity and may explain at least in part the relatively low occurrence of severe hypoglycemia in type 2 diabetes compared with type 1 diabetes where both HGR and RGR counterregulatory responses are reduced.

Mechanisms for the deterioration in glucose tolerance associated with HIV protease inhibitor regimens.

The mechanisms responsible for the deterioration in glucose tolerance associated with protease inhibitor-containing regimens in HIV infection are unclear. Insulin resistance has been implicated as a major factor, but the affected tissues have not been identified. Furthermore, beta-cell function has not been evaluated in detail. The present study was therefore undertaken to assess the effects of protease inhibitor-containing regimens on hepatic, muscle, and adipose tissue insulin sensitivity as well as pancreatic beta-cell function. We evaluated beta-cell function in addition to glucose production, glucose disposal, and free fatty acid (FFA) turnover using the hyperglycemic clamp technique in combination with isotopic measurements in 13 HIV-infected patients before and after 12 weeks of treatment and in 14 normal healthy volunteers. beta-Cell function and insulin sensitivity were also assessed by homeostasis model assessment (HOMA). Treatment increased fasting plasma glucose concentrations in all subjects (P < 0.001). Insulin sensitivity as assessed by HOMA and clamp experiments decreased by approximately 50% (P < 0.003). Postabsorptive glucose production was appropriately suppressed for the prevailing hyperinsulinemia, whereas glucose clearance was reduced (P < 0.001). beta-Cell function decreased by approximately 50% (P = 0.002), as assessed by HOMA, and first-phase insulin release decreased by approximately 25%, as assessed by clamp data (P = 0.002). Plasma FFA turnover and clearance both increased significantly (P < 0.001). No differences at baseline or in responses after treatment were observed between drug naïve patients who were started on a nucleoside reverse transcriptase inhibitor (NRTI) plus a protease inhibitor and patients who had been on long-term NRTI treatment and had a protease inhibitor added. The present study indicates that protease inhibitor-containing regimens impair glucose tolerance in HIV-infected patients by two mechanisms: 1) inducement of peripheral insulin resistance in skeletal muscle and adipose tissue and 2) impairment of the ability of the beta-cell to compensate.