A role for mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) in the regulation of hepatic gluconeogenesis.

Synthesis of phosphoenolpyruvate (PEP) from oxaloacetate is an absolute requirement for gluconeogenesis from mitochondrial substrates. Generally, this reaction has solely been attributed to the cytosolic isoform of PEPCK (PEPCK-C), although loss of the mitochondrial isoform (PEPCK-M) has never been assessed. Despite catalyzing the same reaction, to date the only significant role reported in mammals for the mitochondrial isoform is as a glucose sensor necessary for insulin secretion. We hypothesized that this nutrient-sensing mitochondrial GTP-dependent pathway contributes importantly to gluconeogenesis. PEPCK-M was acutely silenced in gluconeogenic tissues of rats using antisense oligonucleotides both in vivo and in isolated hepatocytes. Silencing PEPCK-M lowers plasma glucose, insulin, and triglycerides, reduces white adipose, and depletes hepatic glycogen, but raises lactate. There is a switch of gluconeogenic substrate preference to glycerol that quantitatively accounts for a third of glucose production. In contrast to the severe mitochondrial deficiency characteristic of PEPCK-C knock-out livers, hepatocytes from PEPCK-M-deficient livers maintained normal oxidative function. Consistent with its predicted role, gluconeogenesis rates from hepatocytes lacking PEPCK-M are severely reduced for lactate, alanine, and glutamine, but not for pyruvate and glycerol. Thus, PEPCK-M has a direct role in fasted and fed glucose homeostasis, and this mitochondrial GTP-dependent pathway should be reconsidered for its involvement in both normal and diabetic metabolism.

Nocturnal Hypoxia Improves Glucose Disposal, Decreases Mitochondrial Efficiency, and Increases Reactive Oxygen Species in the Muscle and Liver of C57BL/6J Mice Independent of Weight Change.

Although acute exposure to hypoxia can disrupt metabolism, longer-term exposure may normalize glucose homeostasis or even improve glucose disposal in the presence of obesity. We examined the effects of two-week exposure to room air (Air), continuous 10% oxygen (C10%), and 12 hr nocturnal periods of 10% oxygen (N10%) on glucose disposal, insulin responsiveness, and mitochondrial function in lean and obese C57BL/6J mice. Both C10% and N10% improved glucose disposal relative to Air in lean and obese mice without evidence of an increase in insulin responsiveness; however, only the metabolic improvements with N10% exposure occurred in the absence of confounding effects of weight loss. In lean mice, N10% exposure caused a decreased respiratory control ratio (RCR) and increased reactive oxygen species (ROS) production in the mitochondria of the muscle and liver compared to Air-exposed mice. In the absence of hypoxia, obese mice exhibited a decreased RCR in the muscle and increased ROS production in the liver compared to lean mice; however, any additional effects of hypoxia in the presence of obesity were minimal. Our data suggest that the development of mitochondrial inefficiency may contribute to metabolic adaptions to hypoxia, independent of weight, and metabolic adaptations to adiposity, independent of hypoxia.

SGLT2 knockout prevents hyperglycemia and is associated with reduced pancreatic ß-cell death in genetically obese mice.

Inhibition of the sodium-glucose co-transporter type 2 (SGLT2) has received growing acceptance as a novel, safe and effective means to improve glycemic control in patients with type 2 diabetes. Inhibition of SGLT2 lowers the renal glucose threshold and reduces plasma glucose by promoting glucose excretion in urine. Both animal studies and clinical trials in man suggest that SGLT2 inhibition has the potential to improve pancreatic ß-cell function by reducing glucose toxicity. However, there is limited data exploring how reducing glucotoxicity via SGLT2 inhibition affects rates of ß-cell proliferation and death throughout life in the context of insulin resistance and type 2 diabetes. SGLT2-/- mice were backcrossed to the db/db strain to produce littermate control db/db-SGLT2+/+ and experimental db/db-SGLT2-/- mice. Mice were euthanized at 5, 12 and 20 weeks of age to collect plasma for glucose, insulin, lipid and cytokine measures, and pancreata for histological analysis including determination of ß-cell mass and rates of proliferation and death. SGLT2 deletion in db/db mice reduced plasma glucose as early as 5 weeks of age and continued throughout life without changes in plasma lipids or cytokines. Reduced plasma glucose levels occurred in parallel with an increase in the relative ß-cell volume and reduced frequency of ß-cell death, and no apparent change in rates of ß-cell proliferation. These data add to a growing body of evidence demonstrating that improved glycemic control achieved through SGLT2 inhibition can preserve ß-cell function and endogenous insulin secretion by reducing glucose toxicity and rates of ß-cell death.

Obstructive sleep apnea in adults with type 1 and type 2 diabetes: perspectives from a quality improvement initiative in a university-based diabetes center.

OBJECTIVE: Obstructive sleep apnea (OSA) and diabetes are frequent comorbid conditions. Screening for OSA in patients with diabetes is recommended but the frequency with which this is done in clinical practice is unknown. The objectives of this quality improvement initiative were to identify clinician and patient perceptions regarding OSA and to identify the prevalence of patients at high risk for OSA (HROSA). METHODS: A quality improvement initiative was conducted to query clinicians and patients attending a specialty diabetes clinic regarding attitudes and beliefs related to OSA. The Berlin Questionnaire was embedded in patient questionnaires to identify patients as low risk for OSA (LROSA) or HROSA. RESULTS: 35 clinicians completed questionnaires with >80% agreement that OSA contributed to blood pressure (BP), glycemic control, and diabetes complications and that screening is a shared responsibility with other physicians; but only 17% indicated regular screening due predominantly to insufficient time. Of 107 patients (26 type 1 diabetes mellitus (T1DM) and 81 type 2 diabetes mellitus (T2DM)), 30% were aware that OSA could affect diabetes outcomes. The prevalence of known OSA, LROSA, and HROSA was similar in T1DM (15%, 50%, 35%) and T2DM (36%, 33%, 31%, respectively) (p=0.21). 59% of all HROSA patients indicated that OSA screening had never been discussed with them. CONCLUSIONS: These results demonstrate that providers, but not patients, are knowledgeable about the importance of OSA screening, but insufficient time is a major barrier to wider screening. Approximately, 30% of patients with T1DM and T2DM were identified as HROSA supporting the need for procedures that improve detection and treatment.

Relationship between sleep disorders and the risk for developing type 2 diabetes mellitus.

Sleep is increasingly being recognized as an important factor in the homeostasis of multiple body functions, including blood glucose metabolism. One of the most common sleep disorders, obstructive sleep apnea, is not only highly prevalent in patients with type 2 diabetes mellitus, but may contribute to the development of abnormalities in blood glucose metabolism. Evidence suggests that effectively treating sleep apnea, specifically with continuous positive airway pressure, improves glycemic and nonglycemic outcomes. Other common sleep disorders, such as insufficient sleep, shift work disorder, and restless legs syndrome, may also have a significant influence on the development and management of diabetes and its complications. The purpose of this article is to review the recent literature on the relationship between sleep disorders and blood glucose metabolism.