Suppression Of Hepatic Glucose Output Research Articles

Approaches to Decrease Hyperglycemia by Targeting Impaired Hepatic Glucose Homeostasis Using Medicinal Plants.

Liver plays a pivotal role in maintaining blood glucose levels through complex processes which involve the disposal, storage, and endogenous production of this carbohydrate. Insulin is the hormone responsible for regulating hepatic glucose production and glucose storage as glycogen, thus abnormalities in its function lead to hyperglycemia in obese or diabetic patients because of higher production rates and lower capacity to store glucose. In this context, two different but complementary therapeutic approaches can be highlighted to avoid the hyperglycemia generated by the hepatic insulin resistance: 1) enhancing insulin function by inhibiting the protein tyrosine phosphatase 1B, one of the main enzymes that disrupt the insulin signal, and 2) direct regulation of key enzymes involved in hepatic glucose production and glycogen synthesis/breakdown. It is recognized that medicinal plants are a valuable source of molecules with special properties and a wide range of scaffolds that can improve hepatic glucose metabolism. Some molecules, especially phenolic compounds and terpenoids, exhibit a powerful inhibitory capacity on protein tyrosine phosphatase 1B and decrease the expression or activity of the key enzymes involved in the gluconeogenic pathway, such as phosphoenolpyruvate carboxykinase or glucose 6-phosphatase. This review shed light on the progress made in the past 7 years in medicinal plants capable of improving hepatic glucose homeostasis through the two proposed approaches. We suggest that Coreopsis tinctoria, Lithocarpus polystachyus, and Panax ginseng can be good candidates for developing herbal medicines or phytomedicines that target inhibition of hepatic glucose output as they can modulate the activity of PTP-1B, the expression of gluconeogenic enzymes, and the glycogen content.

Hypoglycemic Effect of Two Mexican Medicinal Plants.

Type 2 diabetes is a worldwide prevalent disease that is due to a progressive loss of adequate β-cell insulin secretion, frequently against a background of insulin resistance. In Mexican traditional medicine, the therapeutic use of hypoglycemic plants to control the disease is a common practice among type 2 diabetic patients. In the present work, we examined the traditional use of the aerial parts of Eryngium longifolium and the rhizome of Alsophila firma, consumed by people use over the day (in fasting state) to control their blood glucose levels, therefore, we aimed to assess the acute hypoglycemic effect of both plants. First, basic phytochemical profiles of both plants were determined and, subsequently, acute toxicity tests were carried out. Then, in vivo hypoglycemic tests were performed in streptozotocin-nicotinamide (STZ-NA) induced hyperglycemic Wistar rats and finally the effect of the plants on three enzymes involved in glucose metabolism was assayed in vitro. Through HPLC-DAD chromatography, caffeic acid, chlorogenic acid, rosmarinic acid, isoflavones, and glycosylated flavonoids were identified in E. longifolium, while the possible presence of flavanones or dihydroflavonols was reported in A. firma. Both plants exhibited a statistically significant hypoglycemic effect, without a dose-dependent effect. Furthermore, they inhibited glucose 6-phosphatase and fructose 1,6-bisphosphatase in in vitro assays, which could be associated with the hypoglycemic effect in vivo. Thus, this study confirmed for the first time the traditional use of the aerial part of E. longifolium and the rhizome of A. firma as hypoglycemic agents in a hyperglycemic animal model. In addition, it was concluded that their ability to regulate hyperglycemia could involve the inhibition of hepatic glucose output, which mainly controls glucose levels in the fasting state.

Hypoglycemic Effect of Calea urticifolia (Mill.) DC.

The onset of type 2 diabetes (T2D) is a consequence of the progressive loss of adequate β-cell insulin secretion, which frequently occurs under a background of insulin resistance. Currently, nearly 13 million Mexicans are living with diabetes. Moreover, due to poor socioeconomic conditions and the cultural idiosyncrasies of the Mexican population, the use of medicinal plants to treat T2D is a common practice in Mexico. In the Mexican state of Hidalgo, we found the traditional use of Calea urticifolia (CU) to treat this disease. To treat T2D, people drink an infusion made from the aerial part of the plant throughout the day. With the aim of investigating whether the infusion at a traditional dose produces a hypoglycemic effect in either the fasting or postprandial state, we measured the effect of the infusion in a hyperglycemic animal model (rats administered streptozotocin (STZ) and nicotinamide (NZ)) by conducting a glucose tolerance test and constructing a blood-glucose curve. We then analyzed whether the observed effect was related to the inhibition of glucose absorption in the gut or the inhibition of hepatic glucose output (HGO) in vivo and in vitro. Furthermore, we confirmed our findings by identifying the potential targets of the infusion via a network pharmacology analysis. Through high-performance liquid chromatography (HPLC) and thin layer chromatography (TLC), we detected a number of compounds in the extract and identified two of them. The plant extract produced a highly significant hypoglycemic effect under fasting conditions and a weak hypoglycemic effect following glucose or sucrose challenge. Although the plant extract blocked only 20% of the alpha-glucosidase enzyme activity in vitro, in the pyruvate tolerance test (which measures the liberation of hepatic glucose), it significantly reduced glucose levels. Furthermore, in vitro, the extract diminished the activity of the glucose-6-phosphatase complex by 90%. In addition, by conducting TLC, we detected the presence of chlorogenic acid and rutin, which have been reported to block HGO. The results presented here provide evidence of the hypoglycemic effect of the traditionally used C. urticifolia extract and demonstrate that this effect is associated with both a reduction in glucose synthesis via gluconeogenesis due to the phytochemical composition of the extract and a slight blockage of glucose absorption in the gut.

Mechanism of action of Imeglimin: A novel therapeutic agent for type 2 diabetes.

Imeglimin is an investigational first‐in‐class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose‐stimulated insulin secretion (GSIS) and preservation of β‐cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose‐stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD+) via the ‘salvage pathway’. In addition to playing a key role as a mitochondrial co‐factor, NAD+ metabolites may contribute to the increase in GSIS (via enhanced Ca++ mobilization). Imeglimin has also been shown to preserve β‐cell mass in rodents with T2D. Overall, Imeglimin appears to target a key root cause of T2D: defective cellular energy metabolism. This potential mode of action is unique and has been shown to differ from that of other major therapeutic classes, including biguanides, sulphonylureas and glucagon‐like peptide‐1 receptor agonists.

Circulating cathepsin S improves glycaemic control in mice.

Cathepsin S (CTSS) is a cysteine protease that regulates many physiological processes and is increased in obesity and type 2 diabetes. While previous studies show that deletion of CTSS improves glycaemic control through suppression of hepatic glucose output, little is known about the role of circulating CTSS in regulating glucose and energy metabolism. We assessed the effects of recombinant CTSS on metabolism in cultured hepatocytes, myotubes and adipocytes, and in mice following acute CTSS administration. CTSS improved glucose tolerance in lean mice and this coincided with increased plasma insulin. CTSS reduced G6pc and Pck1 mRNA expression and glucose output from hepatocytes but did not affect glucose metabolism in myotubes or adipocytes. CTSS did not affect insulin secretion from pancreatic β-cells, rather CTSS stimulated glucagon-like peptide (GLP)-1 secretion from intestinal mucosal tissues. CTSS retained its positive effects on glycaemic control in mice injected with the GLP1 receptor antagonist Exendin (9-39) amide. The effects of CTSS on glycaemic control were not retained in high-fat-fed mice or db/db mice, despite the preservation of CTSS' inhibitory actions on hepatic glucose output in isolated primary hepatocytes. In conclusion, we unveil a role for CTSS in the regulation of glycaemic control via direct effects on hepatocytes, and that these effects on glycaemic control are abrogated in insulin resistant states.

SMOC1 is a glucose-responsive hepatokine and therapeutic target for glycemic control.

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR (Ghr-391-/-) as for GHR-null (GHR-/-) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase (Pck)-1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.-Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

Acute, local infusion of angiotensin II impairs microvascular and metabolic insulin sensitivity in skeletal muscle.

Angiotensin II (AngII) is a potent vasoconstrictor implicated in both hypertension and insulin resistance. Insulin dilates the vasculature in skeletal muscle to increase microvascular blood flow and enhance glucose disposal. In the present study, we investigated whether acute AngII infusion interferes with insulin's microvascular and metabolic actions in skeletal muscle. Adult, male Sprague-Dawley rats received a systemic infusion of either saline, AngII, insulin (hyperinsulinaemic euglycaemic clamp), or insulin (hyperinsulinaemic euglycaemic clamp) plus AngII. A final, separate group of rats received an acute local infusion of AngII into a single hindleg during systemic insulin (hyperinsulinaemic euglycaemic clamp) infusion. In all animals' systemic metabolic effects, central haemodynamics, femoral artery blood flow, microvascular blood flow, and skeletal muscle glucose uptake (isotopic glucose) were monitored. Systemic AngII infusion increased blood pressure, decreased heart rate, and markedly increased circulating glucose and insulin concentrations. Systemic infusion of AngII during hyperinsulinaemic euglycaemic clamp inhibited insulin-mediated suppression of hepatic glucose output and insulin-stimulated microvascular blood flow in skeletal muscle but did not alter insulin's effects on the femoral artery or muscle glucose uptake. Local AngII infusion did not alter blood pressure, heart rate, or circulating glucose and insulin. However, local AngII inhibited insulin-stimulated microvascular blood flow, and this was accompanied by reduced skeletal muscle glucose uptake. Acute infusion of AngII significantly alters basal haemodynamic and metabolic homeostasis in rats. Both local and systemic AngII infusion attenuated insulin's microvascular actions in skeletal muscle, but only local AngII infusion led to reduced insulin-stimulated muscle glucose uptake. While increased local, tissue production of AngII may be a factor that couples microvascular insulin resistance and hypertension, additional studies are needed to determine the molecular mechanisms responsible for these vascular defects.

Biodistribution, activation, and retention of proinsulin-transferrin fusion protein in the liver: Mechanism of liver-targeting as an insulin prodrug

A recombinant proinsulin-transferrin fusion protein (ProINS-Tf) has been previously reported to be a novel long-lasting INS analog, acting specifically on the inhibition of hepatic glucose output. In this study, we investigated the biodistribution, activation and tissue retention of ProINS-Tf to elucidate its liver targeted anti-diabetic mechanism. The biodistribution study revealed that ProINS-Tf exhibited liver specific accumulation after a single intravenous injection, whereas transferrin (Tf) or insulin (INS) showed relatively even distribution among different organs. The conversion of inactive ProINS-Tf into an active immune-reactive INS-Tf form (irINS-Tf) via a Tf receptor (TfR) mediated process only occurred in the liver, but not in other organs. In addition, ProINS-Tf demonstrated a prolonged retention in the liver after an intravenous injection, suggesting the enhanced association of the bifunctional active form, irINS-Tf, within liver cells. Taken together, our results indicate that ProINS-Tf is a highly liver-targeted INS prodrug with a combination of 3 specific actions in liver cells: (1) TfR-mediated binding and uptake of the prodrug on the cell surface, (2) liver-specific, TfR-mediated conversion of the prodrug into its active form, and (3) the bifunctional binding of the active fusion protein to both Tf and INS receptors in the liver to achieve prolonged retention and thus enhanced anti-diabetic activities.

Sar1, Ile4, Ile8]-angiotensin II Potentiates Insulin Receptor Signalling and Glycogen Synthesis in Hepatocytes.

The angiotensin II type I receptor (AT1R) is involved in the regulation of cardiovascular function. Excessive activation of AT1R by angiotensin II (Ang II) leads to cardiovascular disease and may be involved in the development of insulin resistance and diabetes. Functionally selective Ang II analogues, such as the [Sar1, Ile4, Ile8]-angiotensin II (SII Ang II) analogue, that only activate a subset of signalling networks have been demonstrated to have beneficial effects on cardiovascular function in certain settings, including lowering blood pressure and increasing cardiac performance. Here, we studied the effect of SII Ang II on insulin receptor (IR) signalling and glucose metabolism in primary rat hepatocytes. We show that long-term pre-treatment of hepatocytes with SII Ang II increased insulin-stimulated glycogen synthesis, while Ang II and the AT1R antagonist losartan had no effect. Insulin-stimulated suppression of hepatic glucose output was not affected by Ang II or SII Ang II. It is well known that insulin regulates glycogen synthesis and glucose output through Akt-mediated phosphorylation of glycogen synthase kinase α/β (GSK3α/β) and forkhead box protein O1 (FOXO1), respectively. In line with this, we show that SII Ang II potentiated insulin-stimulated phosphorylation of Akt and GSK3α/β, but not FOXO1. Furthermore, we demonstrate that the effect of SII Ang II on insulin-stimulated signalling and glycogen synthesis was dependent on Src and Gαq, as inhibitors of these proteins abolished the potentiating effect of SII Ang II. Thus, our results demonstrate that SII Ang II may have a positive effect on IR signalling and glucose metabolism in hepatocytes.

Double diabetes: the cardiovascular implications of combining type 1 with type 2 diabetes

Double diabetes: the cardiovascular implications of combining type 1 with type 2 diabetes

Mechanism of Metformin: A Tale of Two Sites

Metformin (dimethylbiguanide) features as a current first-line pharmacological treatment for type 2 diabetes (T2D) in almost all guidelines and recommendations worldwide. It has been known that the antihyperglycemic effect of metformin is mainly due to the inhibition of hepatic glucose output, and therefore, the liver is presumably the primary site of metformin function. However, in this issue of Diabetes Care , Fineman and colleagues (1) demonstrate surprising results from their clinical trials that suggest the primary effect of metformin resides in the human gut. Metformin is an orally administered drug used for lowering blood glucose concentrations in patients with T2D, particularly in those overweight and obese as well as those with normal renal function. Pharmacologically, metformin belongs to the biguanide class of antidiabetes drugs. The history of biguanides can be traced from the use of Galega officinalis (commonly known as galega) for treating diabetes in medieval Europe (2). Guanidine, the active component of galega, is the parent compound used to synthesize the biguanides. Among three main biguanides introduced for diabetes therapy in late 1950s, metformin (Fig. 1 A ) has a superior safety profile and is well tolerated. The other two biguanides, phenformin and buformin, were withdrawn in the early 1970s due to the risk of lactic acidosis and increased cardiac mortality. The incidence of lactic acidosis with metformin at therapeutic doses is rare (less than three cases per 100,000 patient-years) and is not greater than with nonmetformin therapies (3). Major clinical advantages of metformin include specific reduction of hepatic glucose output, with subsequent improvement of peripheral insulin sensitivity, and remarkable cardiovascular safety, but without increasing islet insulin secretion, inducing weight gain, or posing a risk of hypoglycemia. Moreover, metformin has also shown benefits in reducing cancer risk and improving cancer prognosis (4,5), as well as counteracting the cardiovascular complications …

Enhancement of insulin-mediated rat muscle glucose uptake and microvascular perfusion by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside.

BackgroundInsulin-induced microvascular recruitment is important for optimal muscle glucose uptake. 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR, an activator of AMP-activated protein kinase), can also induce microvascular recruitment, at doses that do not acutely activate glucose transport in rat muscle. Whether low doses of AICAR can augment physiologic insulin action is unknown. In the present study we used the euglycemic hyperinsulinemic clamp to assess whether insulin action is augmented by low dose AICAR.MethodsAnesthetized rats were studied during saline infusion or euglycemic insulin (3 mU/kg/min) clamp for 2 h in the absence or presence of AICAR for the last hour (5 mg bolus followed by 3.75 mg/kg/min). Muscle glucose uptake (R’g) was determined radioisotopically with 14C-2-deoxyglucose and muscle microvascular perfusion by contrast-enhanced ultrasound with microbubbles.ResultsAICAR did not affect blood glucose, or lower leg R’g, although it significantly (p < 0.05) increased blood lactate levels and augmented muscle microvascular blood volume via a nitric oxide synthase dependent pathway. Insulin increased femoral blood flow, whole body glucose infusion rate (GIR), R’g, hindleg glucose uptake, and microvascular blood volume. Addition of AICAR during insulin infusion increased lactate production, further increased R’g in Type IIA (fast twitch oxidative) and IIB (fast twitch glycolytic) fiber containing muscles, and hindleg glucose uptake, but decreased R’g in the Type I (slow twitch oxidative) fiber muscle. AICAR also decreased GIR due to inhibition of insulin-mediated suppression of hepatic glucose output. AICAR augmented insulin-mediated microvascular perfusion.ConclusionsAICAR, at levels that have no direct effect on muscle glucose uptake, augments insulin-mediated microvascular blood flow and glucose uptake in white fiber type muscles. Agents targeted to endothelial AMPK activation are promising insulin sensitizers, however, the decrease in GIR and the propensity to increase blood lactate cautions against AICAR as an acute insulin sensitizer.

LTB4 promotes insulin resistance in obese mice by acting on macrophages, hepatocytes and myocytes.

Chronic inflammation is a key component of obesity–induced insulin resistance and plays a central role in metabolic disease. In this study, we found that the major insulin target tissues, liver, muscle and adipose tissue exhibit increased levels of the chemotactic eicosanoid LTB4 in obese high fat diet (HFD) mice compared to lean chow fed mice. Inhibition of the LTB4 receptor, Ltb4r1, through either genetic or pharmacologic loss of function results in an anti–inflammatory phenotype with protection from systemic insulin resistance and hepatic steatosis in the setting of both HFD–induced and genetic obesity. Importantly, in vitro treatment with LTB4 directly enhanced macrophage chemotaxis, stimulated inflammatory pathways in macrophages, promoted de novo hepatic lipogenesis, decreased insulin stimulated glucose uptake in L6 myocytes, increased gluconeogenesis, and impaired insulin–mediated suppression of hepatic glucose output (HGO) in primary mouse hepatocytes. This was accompanied by decreased insulin stimulated Akt phosphorylation and increased Irs1 and Irs2 serine phosphorylation and all of these events were Gαi and Jnk dependent. Taken together, these observations elucidate a novel role of LTB4/Ltb4r1 in the etiology of insulin resistance in hepatocytes and myocytes, and shows that in vivo inhibition of Ltb4r1 leads to robust insulin sensitizing effects.

Dipeptidyl peptidase-4 inhibition ameliorates Western diet-induced hepatic steatosis and insulin resistance through hepatic lipid remodeling and modulation of hepatic mitochondrial function.

Novel therapies are needed for treating the increasing prevalence of hepatic steatosis in Western populations. In this regard, dipeptidyl peptidase-4 (DPP-4) inhibitors have recently been reported to attenuate the development of hepatic steatosis, but the potential mechanisms remain poorly defined. In the current study, 4-week-old C57Bl/6 mice were fed a high-fat/high-fructose Western diet (WD) or a WD containing the DPP-4 inhibitor, MK0626, for 16 weeks. The DPP-4 inhibitor prevented WD-induced hepatic steatosis and reduced hepatic insulin resistance by enhancing insulin suppression of hepatic glucose output. WD-induced accumulation of hepatic triacylglycerol (TAG) and diacylglycerol (DAG) content was significantly attenuated with DPP-4 inhibitor treatment. In addition, MK0626 significantly reduced mitochondrial incomplete palmitate oxidation and increased indices of pyruvate dehydrogenase activity, TCA cycle flux, and hepatic TAG secretion. Furthermore, DPP-4 inhibition rescued WD-induced decreases in hepatic PGC-1α and CPT-1 mRNA expression and hepatic Sirt1 protein content. Moreover, plasma uric acid levels in mice fed the WD were decreased after MK0626 treatment. These studies suggest that DPP-4 inhibition ameliorates hepatic steatosis and insulin resistance by suppressing hepatic TAG and DAG accumulation through enhanced mitochondrial carbohydrate utilization and hepatic TAG secretion/export with a concomitant reduction of uric acid production.

Vascular and metabolic actions of the green tea polyphenol epigallocatechin gallate.

Epidemiological studies demonstrate robust correlations between green tea consumption and reduced risk of type 2 diabetes and its cardiovascular complications. However, underlying molecular, cellular, and physiological mechanisms remain incompletely understood. Health promoting actions of green tea are often attributed to epigallocatechin gallate (EGCG), the most abundant polyphenol in green tea. Insulin resistance and endothelial dysfunction play key roles in the pathogenesis of type 2 diabetes and its cardiovascular complications. Metabolic insulin resistance results from impaired insulin-mediated glucose disposal in skeletal muscle and adipose tissue, and blunted insulin-mediated suppression of hepatic glucose output that is often associated with endothelial/ vascular dysfunction. This endothelial dysfunction is itself caused, in part, by impaired insulin signaling in vascular endothelium resulting in reduced insulin-stimulated production of NO in arteries, and arterioles that regulate nutritive capillaries. In this review, we discuss the considerable body of literature supporting insulin-mimetic actions of EGCG that oppose endothelial dysfunction and ameliorate metabolic insulin resistance in skeletal muscle and liver. We conclude that EGCG is a promising therapeutic to combat cardiovascular complications associated with the metabolic diseases characterized by reciprocal relationships between insulin resistance and endothelial dysfunction that include obesity, metabolic syndrome and type 2 diabetes. There is a strong rationale for well-powered randomized placebo controlled intervention trials to be carried out in insulin resistant and diabetic populations.

Type 2 Diabetes Mellitus in Children and Adolescents

Type 2 Diabetes Mellitus in Children and Adolescents

Type 2 Diabetes Mellitus in Children and Adolescents

On the basis of strong research evidence and consensus, type 1 diabetes mellitus (DM) remains the most common form of DM in children and adolescents. The incidence of type 2 DM in the pediatric population is rapidly increasing because of the obesity epidemic, and minority groups are disproportionately affected. (2) (10) (19) On the basis of some research evidence and consensus, it can be challenging to initially differentiate between type 2 DM and type 1 DM clinically because of the increased prevalence of obesity, the complex interplay of autoimmunity and obesity, and common symptoms at presentation. (1) (10) (19) Significant evidence and consensus support a genetic basis for the development of type 2 DM in children. Physicians should routinely screen at risk children older than age 10 years for DM. Screening criteria include obesity, a family history of type 2 DM, a minority racial or ethnic background, acanthosis nigricans, or other diseases associated with insulin resistance, including polycystic ovary syndrome, hypertension, or dyslipidemia. (1) (10) (18) (19) On the basis of consensus, diagnosis of type 2 DM can be confirmed by an elevated fasting blood glucose level greater than 126 mg/dl (7.0 mmol/L), an elevated 2-hour plasma glucose greater than 200 mg/dL (11.1 mmol/L) on an oral glucose tolerance test, an elevated random blood glucose greater than 200 mg/dL (11.1 mmol/L), or a hemoglobin A1c level greater than 6.5% with suggestive symptoms. (10) According to strong research evidence and consensus, once the diagnosis has been made, treatment should be based on the acuity of presentation and should focus on lifestyle modification and on normalizing hyperglycemia to minimize complications. Metformin is currently first-line treatment for type 2 DM in children and adolescents older than age 10 years who present nonacutely. (18) (19) Strong research evidence and consensus demonstrate that because type 2 DM has an insidious onset, microvascular and macrovascular complications can be present at the time of diagnosis. Patients should be screened for the presence of complications when the diagnosis of type 2 DM is made and in follow-up. (6) (10).

Impairment of insulin-stimulated glucose transport and ERK activation by adipocyte-specific knockout of PKC-λ produces a phenotype characterized by diminished adiposity and enhanced insulin suppression of hepatic gluconeogenesis

Tissue-specific knockout (KO) of atypical protein kinase C-λ (PKC-λ) impairs insulin-stimulated glucose transport in muscle (M) and lipid synthesis in liver (L), thereby producing insulin resistance in MλKO mice and insulin-hypersensitivity in LλKO mice. Here, we generated mice with KO of PKC-λ in adipocytes, i.e., AλKO mice. In isolated adipocytes of AλKO mice, insulin-stimulated aPKC activity and glucose transport were diminished, as were ERK levels and activity. Insulin-stimulated glucose transport and insulin activation of ERK in adipocytes of wild-type mice were similarly inhibited by acute inhibition of PKC-λ with a highly-specific chemical inhibitor. With impairments in glucose transport and ERK activation, AλKO mice had diminished adiposity and serum leptin levels. In addition, AλKO mice had normal glucose tolerance and insulin hypersensitivity owing to enhanced suppression of hepatic glucose output, which apparently reflected increases in Akt activity and FoxO1 phosphorylation, and subsequent decreases in expression of gluconeogenic phosphoenolpyruvate carboxykinase. We conclude that: PKC-λ is required for insulin-stimulated glucose transport and ERK signaling in mouse adipocytes; and diminution of these processes is attended by leanness and therefore hypoleptinemia. How these and perhaps other PKC-λ-dependent processes communicate to liver and improve insulin suppression of hepatic gluconeogenesis remains unclear.

Yacon diet (Smallanthus sonchifolius, Asteraceae) improves hepatic insulin resistance via reducing Trb3 expression in Zucker fa/fa rats

Objective:Yacon is a perennial plant forming a clump of >20 big, edible underground tubers. Yacon, which originates from South America, has become increasingly popular in the Japanese diet for tubers have a lower caloric value and a high fiber content. Recent studies have suggested that yacon feeding ameliorates diabetes as indicated by reduced blood glucose.Methods:We fed male Zucker fa/fa rats for 5 weeks with isocaloric normal chow diet containing from 6.5% control aroid or 6.5% yacon. Insulin sensitivity was evaluated by euglycemic-hyperinsulinemic clamp study.Results:Body weight was comparable between yacon- and aroid-fed rats. In the basal state, yacon feeding had an effect to lower fasting glucose levels from 184.1±4.1 to 167.8±2.7 mg dl−1 (P<0.01), as well as basal hepatic glucose output (HGO) from 9.9±0.4 to 7.4 ± 0.2 mg kg−1 per min (P<0.01). During the clamp studies, the glucose infusion rate required to maintain euglycemia was increased by 12.3% in yacon-fed rat. The insulin suppression of HGO was also increased in yacon-fed rats compared with control rats (85.3±2.4% vs 77.0±3.0% P<0.05), whereas the glucose disposal rate was not different between the two groups. Consistent with the clamp data, the insulin-stimulated phosphorylation of Akt was significantly enhanced in liver but not in skeletal muscle. Furthermore, tribbles 3 (Trb3) expression, which is a negative regulator of Akt activity, was markedly reduced in the liver of yacon-fed rats compared with control rats.Conclusion:These results indicate that the effect of yacon feeding to reduce blood glucose is likely due to its beneficial effects on hepatic insulin sensitivity in the insulin resistant state.