Tag Archives: Glucose

Thyroid Hormone Coordinates Pancreatic Islet Maturation During the Zebrafish Larval-to-Juvenile Transition to Maintain Glucose Homeostasis

Thyroid hormone (TH) signaling promotes tissue maturation and adult organ formation. Developmental transitions alter an organism’s metabolic requirements, and it remains unclear how development and metabolic demands are coordinated. We used the zebrafish as a model to test whether and how TH signaling affects pancreatic islet maturation, and consequently glucose homeostasis, during the larval to juvenile transition. We found that exogenous TH precociously activates the β-cell differentiation genes pax6b and mnx1 while downregulating arxa, a master regulator of α-cell development and function. Together, these effects induced hypoglycemia, at least in part by increasing insulin and decreasing glucagon expression. We visualized TH target tissues using a novel TH-responsive reporter line and found that both α- and β-cells become targets of endogenous TH signaling during the larval-to-juvenile transition. Importantly, endogenous TH is required during this transition for the functional maturation of α- and β-cells in order to maintain glucose homeostasis. Thus, our study sheds new light on the regulation of glucose metabolism during major developmental transitions.

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney

Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium–glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator–activated receptor coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs.

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

A Team-Based Online Game Improves Blood Glucose Control in Veterans With Type 2 Diabetes: A Randomized Controlled Trial

B. Price Kerfoot
Sep 1, 2017; 40:1218-1225
Emerging Technologies and Therapeutics
: Most-Read Full-Text Articles





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

Hypothalamic Ventromedial Lin28a Enhances Glucose Metabolism in Diet-Induced Obesity

The Lin28a/Let-7 axis has been studied in peripheral tissues for its role in metabolism regulation. However, its central function remains unclear. Here we found that Lin28a is highly expressed in the hypothalamus compared with peripheral tissues. Its expression is positively correlated with positive energy balance, suggesting a potential central role for Lin28a in metabolism regulation. Thus, we targeted the hypothalamic ventromedial nucleus (VMH) to selectively overexpress (Lin28aKIVMH) or downregulate (Lin28aKDVMH) Lin28a expression in mice. With mice on a standard chow diet, body weight and glucose homeostasis were not affected in Lin28aKIVMH or Lin28aKDVMH mice. On a high-fat diet, although no differences in body weight and composition were observed, Lin28aKIVMH mice showed improved glucose tolerance and insulin sensitivity compared with controls. Conversely, Lin28aKDVMH mice displayed glucose intolerance and insulin resistance. Changes in VMH AKT activation of diet-induced obese Lin28aKIVMH or Lin28aKDVMH mice were not associated with alterations in Let-7 levels or insulin receptor activation. Rather, we observed altered expression of TANK-binding kinase-1 (TBK-1), which was found to be a direct Lin28a target mRNA. VMH-specific inhibition of TBK-1 in mice with diet-induced obesity impaired glucose metabolism and AKT activation. Altogether, our data show a TBK-1–dependent role for central Lin28a in glucose homeostasis.

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

Altered miR-29 Expression in Type 2 Diabetes Influences Glucose and Lipid Metabolism in Skeletal Muscle

MicroRNAs have emerged as important regulators of glucose and lipid metabolism in several tissues; however, their role in skeletal muscle remains poorly characterized. We determined the effects of the miR-29 family on glucose metabolism, lipid metabolism, and insulin responsiveness in skeletal muscle. We provide evidence that miR-29a and miR-29c are increased in skeletal muscle from patients with type 2 diabetes and are decreased following endurance training in healthy young men and in rats. In primary human skeletal muscle cells, inhibition and overexpression strategies demonstrate that miR-29a and miR-29c regulate glucose uptake and insulin-stimulated glucose metabolism. We identified that miR-29 overexpression attenuates insulin signaling and expression of insulin receptor substrate 1 and phosphoinositide 3-kinase. Moreover, miR-29 overexpression reduces hexokinase 2 expression and activity. Conversely, overexpression of miR-29 by electroporation of mouse tibialis anterior muscle decreased glucose uptake and glycogen content in vivo, concomitant with decreased abundance of GLUT4. We also provide evidence that fatty acid oxidation is negatively regulated by miR-29 overexpression, potentially through the regulation of peroxisome proliferator–activated receptor coactivator-1α expression. Collectively, we reveal that miR-29 acts as an important regulator of insulin-stimulated glucose metabolism and lipid oxidation, with relevance to human physiology and type 2 diabetes.

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men

Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with d-[6,6-2H2]glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis.

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

How Should We Think About the Role of the Brain in Glucose Homeostasis and Diabetes?

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

Indirect Regulation of Endogenous Glucose Production by Insulin: The Single Gateway Hypothesis Revisited

On the basis of studies that investigated the intraportal versus systemic insulin infusion and transendothelial transport of insulin, we proposed the “single gateway hypothesis,” which supposes an indirect regulation of hepatic glucose production by insulin; the rate-limiting transport of insulin across the adipose tissue capillaries is responsible for the slow suppression of free fatty acids (FFAs), which in turn is responsible for delayed suppression of hepatic endogenous glucose production (EGP) during insulin infusion. Preventing the fall in plasma FFAs during insulin infusion either by administering intralipids or by inhibiting adipose tissue lipolysis led to failure in EGP suppression, thus supporting our hypothesis. More recently, mice lacking hepatic Foxo1 in addition to Akt1 and Akt2 (L-AktFoxo1TKO), all required for insulin signaling, surprisingly showed normal glycemia. Inhibiting the fall of plasma FFAs in these mice prevented the suppression of EGP during a clamp, reaffirming that the site of insulin action to control EGP is extrahepatic. Measuring whole-body turnover rates of glucose and FFAs in L-AktFoxo1TKO mice also confirmed that hepatic EGP was regulated by insulin-mediated control of FFAs. The knockout mouse model in combination with sophisticated molecular techniques confirmed our physiological findings and the single gateway hypothesis.

Diabetes Journal current issue





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

New Insulin Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 2 Diabetes Using Basal and Mealtime Insulin: Glucose Control and Hypoglycemia in a 6-Month Randomized Controlled Trial (EDITION 1)

Matthew C. Riddle
Oct 1, 2014; 37:2755-2762
Emerging Technologies and Therapeutics
: Most-Read Full-Text Articles





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon

Roles of the Gut in Glucose Homeostasis

Jens Juul Holst
Jun 1, 2016; 39:884-892
Metabolic Surgery and the Changing Landscape for Diabetes Care
: Most-Read Full-Text Articles





  • Twitter
  • del.icio.us
  • Digg
  • Facebook
  • Technorati
  • Reddit
  • Yahoo Buzz
  • StumbleUpon