Targeting glucagon receptor signalling in treating metabolic syndrome and renal injury in Type 2 diabetes: theory versus promise

Pancreatic bi-hormones insulin and glucagon are the Yin and Yang in the regulation of glucose metabolism and homoeostasis. Insulin is synthesized primarily by pancreatic β-cells and is released in response to an increase in blood glucose levels (hyperglycaemia). By contrast, glucagon is synthesized by pancreatic α-cells and is released in response to a decrease in blood glucose (hypoglycaemia). The principal role of glucagon is to counter the actions of insulin on blood glucose homoeostasis, but it also has diverse non-hyperglycaemic actions. Although Type 1 diabetes is caused by insulin deficiency (insulin-dependent) and can be corrected by insulin replacement, Type 2 diabetes is a multifactorial disease and its treatment is not dependent on insulin therapy alone. Type 2 diabetes in humans is characterized by increased insulin resistance, increased fasting blood glucose, impaired glucose tolerance and the development of glomerular hyperfiltration and microalbuminuria, ultimately leading to diabetic nephropathy and end-stage renal disease. Clinical studies have suggested that an inappropriate increase in hyperglycaemic glucagon (hyperglucagonaemia) over hypoglycaemic insulin (not insulin deficiency until advanced stages) plays an important role in the pathogenesis of Type 2 diabetes. However, for decades, research efforts and resources have been devoted overwhelmingly to studying the role of insulin and insulin-replacement therapy. By contrast, the implication of glucagon and its receptor signalling in the development of Type 2 diabetic metabolic syndromes and end-organ injury has received little attention. The aim of this review is to examine the evidence as to whether glucagon and its receptor signalling play any role(s) in the pathogenesis of Type 2 diabetic renal injury, and to explore whether targeting glucagon receptor signalling remains only a theoretical antidiabetic strategy in Type 2 diabetes or may realize its promise in the future.

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Pivotal Role of Timely Basal Insulin Replacement After Metformin Failure in Sustaining Long-Term Blood Glucose Control at a Target in Type 2 Diabetes

Diabetes Care ◽

10.2337/dc11-s224 ◽

2011 ◽

Vol 34 (Supplement_2) ◽

pp. S220-S224 ◽

Cited By ~ 7

Author(s):

G. B. Bolli ◽

P. Lucidi ◽

F. Porcellati ◽

C. G. Fanelli

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Glucose Control ◽

Basal Insulin ◽

Blood Glucose Control ◽

Pivotal Role ◽

Insulin Replacement

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An anxiolytic drug buspirone ameliorates hyperglycemia and endothelial dysfunction in type 2 diabetic rat model

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0224 ◽

2020 ◽

Vol 45 (4) ◽

pp. 397-404

Author(s):

Tugba Gurpinar Çavuşoğlu ◽

Ertan Darıverenli ◽

Kamil Vural ◽

Nuran Ekerbicer ◽

Cevval Ulman ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Fasting Blood Glucose ◽

Diabetic Rats ◽

Diabetic Rat ◽

Insulin Levels ◽

Type 2 Diabetic

AbstractObjectivesType 2 diabetes is a common metabolic disease and anxiety disorders are very common among diabetics. Buspirone is used in the treatment of anxiety, also having blood glucose-lowering effects. The aim of the study was to investigate the effects of buspirone on the glucose and lipid metabolism as well as vascular function in type 2 diabetic rats.MethodsA type 2-diabetic model was induced through a high-fat diet for eight weeks followed by the administration of low-dose streptozotocin (35 mg/kg, intraperitoneal) in rats. Buspirone was given at two different doses (1.5 mg/kg/d and 5 mg/kg/d) and combined with metformin (300 mg/kg/d). The fasting glucose and insulin levels, lipid profile were analyzed, and vascular response measured from the thoracic aorta was also evaluated.ResultsBoth doses of buspirone caused a significant improvement in fasting blood glucose levels. In particular, the buspirone treatment, combined with metformin, improved endothelial dysfunction and was found to be correlated with decreased nitrate/nitrite levels.ConclusionsBuspirone may be effective in the treatment of type 2 diabetes, either alone or in combination with other treatments, particularly in terms of endothelial dysfunction, inflammation and impaired blood glucose, and insulin levels.

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Study on the prevalence of dyslipidemia in type 2 diabetes mellitus

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20192239 ◽

2019 ◽

Vol 6 (3) ◽

pp. 786

Author(s):

Eda Dayakar ◽

C. Sathya Sree ◽

E. Sanjay

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Type 2 Diabetes Mellitus ◽

Blood Glucose ◽

Diabetic Patients ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Type 2 Diabetic

Background: Diabetes mellitus is a common health problem globally. Dyslipidaemia is a major risk factor to develop cardiovascular disease in diabetics. They present study was undertaken to find out the prevalence of dyslipidaemia in type 2 diabetic patients.Methods: The present study was a cross sectional study consisting of 46 (23 male and 23 female) known type 2 diabetes mellitus patients. Age, gender, duration of diabetes, body mass index (BMI) was recorder in all the diabetic patients. Fasting blood glucose levels, total cholesterol, triglycerides, HDL, LDL, VLDL levels were measured using standard methods and recorded.Results: The average total cholesterol, triglycerides, LDL, HDL and VLDL were 200±42mg/dl, 169.62±89.79mg/dl, 132.45±36.38mg/dl,39.1±16.6mg/dl and 35.85±17.09mg/dl respectively. The incidence of occurrence of hypercholesterolemia was 58.6% and hypertriglyceridemia 36.9%. Increased levels of LDL were observed in 30 (65.2%) patients and reduced HDL was observed in 43 (93.4%) patients. The incidence rate of dyslipidaemia was higher in female diabetic patients when compared to male diabetic patients.Conclusions: Awareness on the dyslipidaemia and its risk factors should be provided to the type 2 diabetic patients as they are more prone to get cardiovascular disease and lipid profile also should be monitored regularly along with blood glucose levels.

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Long-term hyperglucagonaemia induces early metabolic and renal phenotypes of Type 2 diabetes in mice

Clinical Science ◽

10.1042/cs20070257 ◽

2008 ◽

Vol 114 (9) ◽

pp. 591-601 ◽

Cited By ~ 17

Author(s):

Xiao C. Li ◽

Tang-dong Liao ◽

Jia L. Zhuo

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Glucose Tolerance ◽

Serum Insulin ◽

Fasting Blood Glucose ◽

Weight Ratio ◽

Glomerular Injury ◽

Glucagon Receptor

Clinical studies have shown that patients with early Type 2 diabetes often have elevated serum glucagon rather than insulin deficiency. Imbalance of insulin and glucagon in favouring the latter may contribute to impaired glucose tolerance, persistent hyperglycaemia, microalbuminuria and glomerular injury. In the present study, we tested the hypothesis that long-term glucagon infusion induces early metabolic and renal phenotypes of Type 2 diabetes in mice by activating glucagon receptors. Five groups of adult male C57BL/6J mice were treated with vehicle, glucagon alone (1 μg/h via an osmotic minipump, intraperitoneally), glucagon plus the glucagon receptor antagonist [Des-His1-Glu9]glucagon (5 μg/h via an osmotic minipump), [Des-His1-Glu9]glucagon alone or a high glucose load alone (2% glucose in the drinking water) for 4 weeks. Glucagon infusion increased serum glucagon by 129% (P<0.05), raised systolic BP (blood pressure) by 21 mmHg (P<0.01), elevated fasting blood glucose by 42% (P<0.01), impaired glucose tolerance (P<0.01), increased the kidney weight/body weight ratio (P<0.05) and 24 h urinary albumin excretion by 108% (P<0.01) and induced glomerular mesangial expansion and extracellular matrix deposition. These responses were associated with marked increases in phosphorylated ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt signalling proteins in the liver and kidney (P<0.01). Serum insulin did not increase proportionally. Concurrent administration of [Des-His1-Glu9]glucagon with glucagon significantly attenuated glucagon-increased BP, fasting blood glucose, kidney weight/body weight ratio and 24 h urinary albumin excretion. [Des-His1-Glu9]glucagon also improved glucagon-inpaired glucose tolerance, increased serum insulin by 56% (P<0.05) and attenuated glomerular injury. However, [Des-His1-Glu9]glucagon or high glucose administration alone did not elevate fasting blood glucose levels, impair glucose tolerance or induce renal injury. These results demonstrate for the first time that long-term hyperglucagonaemia in mice induces early metabolic and renal phenotypes of Type 2 diabetes by activating glucagon receptors. This supports the idea that glucagon receptor blockade may be beneficial in treating insulin resistance and Type 2 diabetic renal complications.

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Consumption of Whole Eggs Promotes Insulin Sensitivity in Db/db Mice (OR34-01-19)

Current Developments in Nutrition ◽

10.1093/cdn/nzz031.or34-01-19 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

Author(s):

Peiran Lu ◽

Lei Wu ◽

Xin Guo ◽

Siau Yen Wong ◽

Stephen Clarke ◽

...

Keyword(s):

Type 2 Diabetes ◽

Blood Glucose ◽

Insulin Sensitivity ◽

Cholesterol Synthesis ◽

Respiratory Activity ◽

High Cholesterol ◽

Egg Consumption ◽

Type 2 Diabetic ◽

Mitochondrial Respiratory Activity

Abstract Objectives Chicken eggs have a high nutrient density. Some country guidelines recommend that people with type 2 diabetes (T2D) limit their consumption of eggs due to its high cholesterol content. However, several clinical studies showed that egg intake is associated with a lower risk of type 2 diabetes. In the current study, we sought to explore whether egg consumption improves insulin sensitivity and subsequent blood glucose management in type 2 diabetic db/db mice. Methods Six-week-old male db/db mice were fed a low-fat diet (LFD, 10 kCal % from fat) or LFD supplemented with 1% whole eggs (Egg) for 8 weeks. At the termination of the study, mice were fasted for 3 hrs prior to euthanization. Blood and other tissues were collected for laboratory assessments. Plasma metabolic parameters and pro-inflammatory cytokines were monitored by a clinical analyzer and ELISA, respectively. Hepatic and skeletal muscle mitochondrial respiratory activity was assessed by a Seahorse XFe Analyzer. Hepatic gene expression was analyzed by transcriptomics and confirmed by real-time PCR and/or Western blot. Results Egg consumption significantly increased body weight gain, lowered fasting blood glucose, insulin, and IL-6 levels, and elevated total cholesterol, HDL, LDL, and GLP-1 levels. Only the basal mitochondrial respiratory activity was decreased, and the complex II respiratory activity was increased in gastrocnemius muscles in mice fed Egg. Hepatic mitochondrial activity was not altered by diet. Mechanistically, transcriptomics results revealed that hepatic genes involved in enhanced insulin sensitivity were highly expressed, but genes in endogenous cholesterol synthesis were significantly suppressed after egg consumption. Conclusions The results suggest that egg consumption is beneficial to blood glucose control in type 2 diabetic mice. Type 2 diabetic animal could manage the cholesterol level through suppression of de novo cholesterol synthesis when consuming a high cholesterol diet, e.g., egg diet. Funding Sources National egg nutrition center grant USDA NIFA grant

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Reduction of islet pyruvate carboxylase activity might be related to the development of type 2 diabetes mellitus in Agouti-K mice

Journal of Endocrinology ◽

10.1677/joe-09-0391 ◽

2009 ◽

Vol 204 (2) ◽

pp. 143-152 ◽

Cited By ~ 19

Author(s):

J Han ◽

Y Q Liu

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Blood Glucose ◽

Protein Level ◽

Pyruvate Carboxylase ◽

Β Cell ◽

Cell Adaptation ◽

Type 2 Diabetic

Pyruvate carboxylase (PC) activity is enhanced in the islets of obese rats, but it is reduced in the islets of type 2 diabetic rats, suggesting the importance of PC in β-cell adaptation to insulin resistance as well as the possibility that PC reduction might lead to hyperglycemia. However, the causality is currently unknown. We used obese Agouti mice (AyL) as a model to show enhanced β-cell adaptation, and type 2 diabetic db/db mice as a model to show severe β-cell failure. After comparison of the two models, a less severe type 2 diabetic Agouti-K (AyK) mouse model was used to show the changes in islet PC activity during the development of type 2 diabetes mellitus (T2DM). AyK mice were separated into two groups: mildly (AyK-M, blood glucose <250 mg/dl) and severely (AyK-S, blood glucose >250 mg/dl) hyperglycemic. Islet PC activity, but not protein level, was increased 1.7-fold in AyK-M mice; in AyK-S mice, islet PC activity and protein level were reduced. All other changes including insulin secretion and islet morphology in AyK-M mice were similar to those observed in AyL mice, but they were worse in AyK-S mice where these parameters closely matched those in db/db mice. In 2-day treated islets, PC activity was inhibited by high glucose but not by palmitate. Our findings suggest that islet PC might play a role in the development of T2DM where reduction of PC activity might be a consequence of mild hyperglycemia and a cause for severe hyperglycemia.

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