Regulation of the Cortisol Axis, Glucagon, and Growth Hormone by Glucose Is Altered in Prediabetes and Type 2 Diabetes.

CONTEXT: Insulin-antagonistic, counter-regulatory hormones have been implicated in the development of type 2 diabetes (T2D). OBJECTIVE: In this cross-sectional study, we investigated whether glucose-dependent regulation of such hormones differ in individuals with T2D, prediabetes (PD), and normoglycemia (NG). METHODS: Fifty-four individuals with or without T2D underwent one hyperinsulinemic-normoglycemic-hypoglycemic and one hyperglycemic clamp with repeated hormonal measurements. Participants with T2D (n = 19) were compared with a group-matched (age, sex, BMI) subset of participants without diabetes (ND, n = 17), and also with participants with PD (n = 18) and NG (n = 17). RESULTS: In T2D vs ND, glucagon levels were higher and less suppressed during the hyperglycemic clamp whereas growth hormone (GH) levels were lower during hypoglycemia (P < .05). Augmented ACTH response to hypoglycemia was present in PD vs NG (P < .05), with no further elevation in T2D. In contrast, glucagon and GH alterations were more marked in T2D vs PD (P < .05).In the full cohort (n = 54), augmented responses of glucagon, cortisol, and ACTH and attenuated responses of GH correlated with adiposity, dysglycemia, and insulin resistance. In multilinear regressions, insulin resistance was the strongest predictor of elevated hypoglycemic responses of glucagon, cortisol, and ACTH. Conversely, fasting glucose and HbA1c were the strongest predictors of low GH levels during hypoglycemia and elevated, i.e. less suppressed glucagon levels during hyperglycemia, respectively. Notably, adiposity measures were also strongly associated with the responses above. CONCLUSIONS: Altered counter-regulatory hormonal responses to glucose variations are observed at different stages of T2D development and may contribute to its progression by promoting insulin resistance and dysglycemia.

Endocrinological evaluation of dawn phenomenon in patients with diabetes and comparison of insulin glargine U-100 biosimilar (Insulin Glargine BS Injection "Lilly") and glargine U-300 (Lantus XR): a randomized controlled study.

We investigated the pathophysiology of the dawn phenomenon by examining the effects of changes in blood glucose levels from late night to early morning on various hormones in a group taking glargine BS and a group taking Lantus XR, with the goal of achieving better glycemic control. Patients with types 1 and 2 diabetes scheduled for inpatient education were divided into BS and XR groups. Blood glucose levels were tracked from 0:00 to 7:00, while blood samples were extracted at 3:00 and 7:00 to measure glucose levels and hormones related to the dawn phenomenon. Overall, we analyzed blood sample and intermittently scanned Continuous Glucose Monitoring data of 43 and 40 patients, respectively. From 0:00 to 7:00, the mean blood glucose was significantly lower in the BS group, although the fluctuation was similar (p < 0.0001). The BS group also exhibited significantly higher ∆ACTH (p = 0.0215) and ∆ cortisol (p = 0.0430) than the XR group. In the BS group, ∆Glu exhibited a significant negative correlation with ∆ACTH and ∆cortisol (p = 0.0491). Similar findings were not observed in the XR group. These results suggest that XR may be a better choice for long-acting insulin since it is less likely to induce cortisol secretion. Further, analysis of the dawn phenomenon and non-dawn phenomenon groups showed the mean CPR levels at 3:00 and 7:00 were significantly higher in the latter (p = 0.0135). This supports the conventional belief that appropriate basal insulin replacement therapy is a beneficial treatment for the dawn phenomenon.

Pathophysiology and management of hypoglycemia in diabetes.

In the century since the discovery of insulin, diabetes has changed from an early death sentence to a manageable chronic disease. This change in longevity and duration of diabetes coupled with significant advances in therapeutic options for patients has fundamentally changed the landscape of diabetes management, particularly in patients with type 1 diabetes mellitus. However, hypoglycemia remains a major barrier to achieving optimal glycemic control. Current understanding of the mechanisms of hypoglycemia has expanded to include not only counter-regulatory hormonal responses but also direct changes in brain glucose, fuel sensing, and utilization, as well as changes in neural networks that modulate behavior, mood, and cognition. Different strategies to prevent and treat hypoglycemia have been developed, including educational strategies, new insulin formulations, delivery devices, novel technologies, and pharmacologic targets. This review article will discuss current literature contributing to our understanding of the myriad of factors that lead to the development of clinically meaningful hypoglycemia and review established and novel therapies for the prevention and treatment of hypoglycemia.

Counter-regulatory responses to Telfairia occidentalis-induced hypoglycaemia.

BACKGROUND: Telfairia occidentalis (TO) has many biological activities including blood glucose regulation. Thus, it is being used in the treatment of diabetes mellitus. TO has been shown to cause insulin-mediated hypoglycaemia, which leads to post-hypoglycaemic hyperglycaemia. However, the mechanism involved in the post-hypoglycaemic hyperglycaemia is still poorly understood. OBJECTIVE: This research was designed to determine the response of glucoregulatory hormones and enzymes to TO treatment. METHODS: Thirty-five male Wistar rats were divided into seven oral treatment groups (n = 5/group), which received either of 100 mg/kg or 200 mg/kg TO for 7-, 10- or 14 days. RESULTS: The 7-day treatment with TO significantly increased the levels of insulin, glucagon, and glucose-6-phosphatase (G6Pase) activity but decreased the levels of glucose, adrenaline, and glucokinase (GCK) activity. The 10-day treatment with 100 mg/kg TO increased glucose and decreased GCK activity while 200 mg/kg for the same duration increased glucose, insulin, GCK and G6Pase activities but reduced glucagon. The 14-day treatment with 100 mg/kg TO decreased glucose and glucagon but increased cortisol, while 200 mg/kg TO for same duration increased insulin, but reduced glucagon and GCK activity. CONCLUSION: The TO's post-hypoglycaemic hyperglycaemia results from increased glucagon and G6Pase activity, and reduced GCK activity. Moreover, the glucagon response mainly depends on glucose rather than insulin.

The Central Role of Glucokinase in Glucose Homeostasis: A Perspective 50 Years After Demonstrating the Presence of the Enzyme in Islets of Langerhans.

It is hypothesized that glucokinase (GCK) is the glucose sensor not only for regulation of insulin release by pancreatic ß-cells, but also for the rest of the cells that contribute to glucose homeostasis in mammals. This includes other cells in endocrine pancreas (α- and δ-cells), adrenal gland, glucose sensitive neurons, entero-endocrine cells, and cells in the anterior pituitary. Glucose transport is by facilitated diffusion and is not rate limiting. Once inside, glucose is phosphorylated to glucose-6-phosphate by GCK in a reaction that is dependent on glucose throughout the physiological range of concentrations, is irreversible, and not product inhibited. High glycerol phosphate shuttle, pyruvate dehydrogenase, and pyruvate carboxylase activities, combined with low pentose-P shunt, lactate dehydrogenase, plasma membrane monocarboxylate transport, and glycogen synthase activities constrain glucose-6-phosphate to being metabolized through glycolysis. Under these conditions, glycolysis produces mostly pyruvate and little lactate. Pyruvate either enters the citric acid cycle through pyruvate dehydrogenase or is carboxylated by pyruvate carboxylase. Reducing equivalents from glycolysis enter oxidative phosphorylation through both the glycerol phosphate shuttle and citric acid cycle. Raising glucose concentration increases intramitochondrial [NADH]/[NAD+] and thereby the energy state ([ATP]/[ADP][Pi]), decreasing [Mg2+ADP] and [AMP]. [Mg2+ADP] acts through control of KATP channel conductance, whereas [AMP] acts through regulation of AMP-dependent protein kinase. Specific roles of different cell types are determined by the diverse molecular mechanisms used to couple energy state to cell specific responses. Having a common glucose sensor couples complementary regulatory mechanisms into a tightly regulated and stable glucose homeostatic network.

Adrenaline and cortisol levels are lower during nighttime than daytime hypoglycaemia in children with type 1 diabetes.

AIM: We investigated children's counter regulatory hormone profiles during a hyperinsulinaemic hypoglycaemic clamp procedure at day and night. METHODS: In 2013, we assessed the counter regulatory response to hypoglycaemia in eight outpatients with type 1 diabetes, recruited from the Herlev Hospital, Denmark, at a mean age of 9.6 ± 2.3 years. Hyperinsulinaemic 80 mU/m2 /min clamps were performed with a stepwise reduction in plasma glucose from euglycaemia (7-9 mmol/L) to hypoglycaemia (<3.5 mmol/L) and the glucose nadir (≤2.2 mmol/L) during the day and night. Adrenaline, cortisol, glucagon and growth hormone levels were assessed. RESULTS: Adrenaline and growth hormone levels were higher during the day versus the night (p = 0.04 and p = 0.01, respectively). However, at the glucose nadir, the level of adrenaline was lower during the night than the day (0.6 ± 0.2 versus 1.9 ± 0.5 nmol/L, p = 0.016) and cortisol was lower during the day than the night (42 ± 15 versus 319 ± 81 nmol/L, p = 0.016). No differences were demonstrated for glucagon and growth hormone levels based on the same criteria. CONCLUSION: The adrenaline response was blunted during nocturnal iatrogenic hypoglycaemia in our study cohort, and no increase in cortisol levels was demonstrated.

Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome.

CONTEXT: Premenopausal women have blunted counter-regulatory hormone responses (CRR) to hypoglycemia compared to men. Postmenopausal women have CRR similar to men; the premenopausal pattern can be restored by estrogen. However, glucagon and pancreatic polypeptide (PP) responses remain lower in postmenopausal women than in men. Since hyperandrogenemia contributes to the metabolic phenotype of polycystic ovary syndrome (PCOS), we hypothesize that CRR to hypoglycemia especially of glucagon and PP is exaggerated in premenopausal women with PCOS compared to premenopausal control women. STUDY SUBJECTS AND METHODS: Ten obese women with PCOS and 9 control women of similar ethnicity, age and BMI underwent determination of CRR in response to hypoglycemia during 180-min 60mU/m2/min insulin dose hypoglycemic clamp with isotopic assessment of endogenous glucose production (EGP). To assess CRR to hypoglycemia, glucagon, cortisol, growth hormone (GH), epinephrine, norepinephrine, PP, lactate, free fatty acid (FFA), ß-hydroxybutyrate, and glycerol levels were sampled at 15-min intervals throughout the clamp. MAIN FINDINGS: Incremental glucagon levels were ~3-fold higher during hypoglycemia (P=0.03) in PCOS. Postabsorptive, steady-state and incremental GH, cortisol, epinephrine, norepinephrine, PP, FFA, glycerol and ß-hydroxybutyrate did not differ. At target glucose levels of ~52mg/dL, insulin mediated glucose disposal (IMGD) was decreased by ~40% (P=0.02) in PCOS, compared to control women, despite ~20% higher steady-state insulin levels (P=0.03). Neither postabsorptive nor steady-state EGP differed. However, postabsorptive lactate levels were ~50% higher (P=0.02). PCOS status (P=0.04) and IMGD (P=0.02) predicted the differential glucagon response to hypoglycemia in separate regression models, however, neither parameter remained an independent predictor in a combined model. PRINCIPAL CONCLUSIONS: Glucagon responses were increased in PCOS, whereas other CRR did not differ. Women with PCOS were insulin resistant under hypoglycemic conditions and higher postabsorptive lactate levels in PCOS were consistent with this finding. Insulin resistance may have contributed to exaggerated glucagon response to hypoglycemia in PCOS.

Chromium supplementation improved post-stroke brain infarction and hyperglycemia.

Hyperglycemia is common after acute stroke and is associated with a worse outcome of stroke. Thus, a better understanding of stress hyperglycemia is helpful to the prevention and therapeutic treatment of stroke. Chromium is an essential nutrient required for optimal insulin activity and normal carbohydrate and lipid metabolism. Beyond its nutritional effects, dietary supplement of chromium causes beneficial outcomes against several diseases, in particular diabetes-associated complications. In this study, we investigated whether post-stroke hyperglycemia involved chromium dynamic mobilization in a rat model of permanent focal cerebral ischemia and whether dietary supplement of chromium improved post-stroke injury and alterations. Stroke rats developed brain infarction, hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance. Post-stroke hyperglycemia was accompanied by elevated secretion of counter-regulatory hormones including glucagon, corticosterone, and norepinephrine, decreased insulin signaling in skeletal muscles, and increased hepatic gluconeogenesis. Correlation studies revealed that counter-regulatory hormone secretion showed a positive correlation with chromium loss and blood glucose increased together with chromium loss. Daily chromium supplementation increased tissue chromium levels, attenuated brain infarction, improved hyperglycemia, and decreased plasma levels of glucagon and corticosterone in stroke rats. Our findings suggest that stroke rats show disturbance of tissue chromium homeostasis with a net loss through urinary excretion and chromium mobilization and loss might be an alternative mechanism responsible for post-stroke hyperglycemia.