Inhibitors of sodium-glucose cotransporter 2 (SGLT2) are a novel class of antidiabetes drugs, and members of this class are under various stages of clinical development for the management of type 2 ...diabetes mellitus (T2DM). It is widely accepted that SGLT2 is responsible for >80% of the reabsorption of the renal filtered glucose load. However, maximal doses of SGLT2 inhibitors fail to inhibit >50% of the filtered glucose load. Because the clinical efficacy of this group of drugs is entirely dependent on the amount of glucosuria produced, it is important to understand why SGLT2 inhibitors inhibit <50% of the filtered glucose load. In this Perspective, we provide a novel hypothesis that explains this apparent puzzle and discuss some of the clinical implications inherent in this hypothesis.
Hyperglycemia plays an important role in the pathogenesis of type 2 diabetes mellitus, i.e., glucotoxicity, and it also is the major risk factor for microvascular complications. Thus, effective ...glycemic control will not only reduce the incidence of microvascular complications but also correct some of the metabolic abnormalities that contribute to the progression of the disease. Achieving durable tight glycemic control is challenging because of progressive β-cell failure and is hampered by increased frequency of side effects, e.g., hypoglycemia and weight gain. Most recently, inhibitors of the renal sodium-glucose cotransporter have been developed to produce glucosuria and reduce the plasma glucose concentration. These oral antidiabetic agents have the potential to improve glycemic control while avoiding hypoglycemia, to correct the glucotoxicity, and to promote weight loss. In this review, we will summarize the available data concerning the mechanism of action, efficacy, and safety of this novel antidiabetic therapeutic approach.
Hyperglycemia is the primary factor responsible for the microvascular, and to a lesser extent macrovascular, complications of diabetes. Despite this well-established relationship, approximately half ...of all type 2 diabetic patients in the US have a hemoglobin A1c (HbA1c) ≥7.0%. This is associated in part with the side effects, i.e., weight gain and hypoglycemia, of currently available antidiabetic agents and in part with the failure to utilize medications that reverse the basic pathophysiological defects present in patients with type 2 diabetes. The kidney has been shown to play a central role in the development of hyperglycemia by excessive production of glucose throughout the sleeping hours and enhanced reabsorption of filtered glucose by the renal tubules secondary to an increase in the threshold at which glucose spills into the urine. Recently, a new class of antidiabetic agents, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, has been developed and approved for the treatment of patients with type 2 diabetes. In this review, we examine their mechanism of action, efficacy, safety, and place in the therapeutic armamentarium. Since the SGLT2 inhibitors have a unique mode of action that differs from all other oral and injectable antidiabetic agents, they can be used at all stages of the disease and in combination with all other antidiabetic medications.
Contributions of β-Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired
Fasting Glucose
Muhammad A. Abdul-Ghani , MD, PHD ,
Devjit Tripathy , MD, PHD ...and
Ralph A. DeFronzo , MD
Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas
Address correspondence and reprint requests to Muhammad Abdul-Ghani, Division of Diabetes, University of Texas Health Science
Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail: albarado{at}uthscsa.edu
Abstract
Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are intermediate states in glucose metabolism that exist
between normal glucose tolerance and overt diabetes. Epidemiological studies demonstrate that the two categories describe
distinct populations with only partial overlap, suggesting that different metabolic abnormalities characterize IGT and IFG.
Insulin resistance and impaired β-cell function, the primary defects observed in type 2 diabetes, both can be detected in
subjects with IGT and IFG. However, clinical studies suggest that the site of insulin resistance varies between the two disorders.
While subjects with IGT have marked muscle insulin resistance with only mild hepatic insulin resistance, subjects with IFG
have severe hepatic insulin resistance with normal or near-normal muscle insulin sensitivity. Both IFG and IGT are characterized
by a reduction in early-phase insulin secretion, while subjects with IGT also have impaired late-phase insulin secretion.
The distinct metabolic features present in subjects with IFG and IGT may require different therapeutic interventions to prevent
their progression to type 2 diabetes.
AIR, acute insulin response
CGI, combined glucose intolerance
FPG, fasting plasma glucose
FPI, fasting plasma insulin
GIP, glucose-dependent insulinotrophic peptide
GLP-1, glucagon-like peptide-1
HOMA-IR, homeostasis model assessment of insulin resistance
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
IVGTT, intravenous glucose tolerance test
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
Footnotes
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted January 26, 2006.
Received November 8, 2005.
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Context:
The Centers for Disease Control and Prevention estimates that there are approximately 79,000,000 individuals in the United States with prediabetes impaired glucose tolerance (IGT) and/or ...impaired fasting glucose and that approximately 40–50% will progress to type 2 diabetes mellitus (T2DM) during their lifetime. Therefore, treatment of high-risk IGT individuals to prevent T2DM has important medical, economic, social, and human implications. Individuals in the upper tertile of IGT are maximally/near-maximally insulin resistant, have lost 70–80% of their β-cell function, and have approximately a 10% incidence of diabetic retinopathy. Therefore, preservation of the remaining 20–30% of β-cell function is critical to prevent future development of T2DM.
Evidence Acquisition:
We searched MEDLINE from 2000 to the present to identify placebo-controlled trials in which individuals with IGT received pharmacological therapy to prevent progression to diabetes.
Evidence Synthesis:
Lifestyle modification reduces IGT conversion to T2DM, but it is difficult to implement and maintain. Moreover, 40–50% of IGT subjects progress to T2DM despite weight loss. In contrast, pharmacological intervention with medications that reverse known pathophysiological abnormalities (β-cell dysfunction and insulin resistance) uniformly prevents IGT progression to T2DM. Thiazolidinediones reduce IGT conversion to diabetes by approximately 50–70%. Metformin in the U.S. Diabetes Prevention Program reduced the development of T2DM by 31% and has been recommended by the American Diabetes Association. Because glucagon-like peptide-1 analogs augment insulin secretion, preserve β-cell function, and promote weight loss, they may be efficacious in preventing IGT progression to T2DM.
Conclusion:
Pharmacological intervention with a variety of agents (thiazolidinediones, metformin, acarbose, glucagon-like peptide-1 analogs) consistently reduces the rate of conversion of IGT to T2DM.
Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM ...patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited 2‐14C‐pyruvate oxidation and pyruvate‐driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose‐dependently inhibited pyruvate‐driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate‐driven ATP synthesis, but did not alter pyruvate‐driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary, these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies.
The thiazolidinedione drug pioglitazone inhibits multiple pathways of pyruvate metabolism in cultured hepatocytes, providing a direct mechanism through which it may exert its antidiabetic effects in the liver. These effects occur independently from the putative mitochondrial pyruvate carrier proteins MPC1 and MPC2, raising new speculation about the role of these proteins in pyruvate metabolism and TZD action.
OBJECTIVE:--To derive indexes for muscle and hepatic insulin sensitivity from the measurement of plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT). RESEARCH ...DESIGN AND METHODS--A total of 155 subjects of Mexican-American origin (58 male and 97 female, aged 18-70 years, BMI 20-65 kg/m²) with normal glucose tolerance (n = 100) or impaired glucose tolerance (n = 55) were studied. Each subject received a 75-g OGTT and a euglycemic insulin clamp in combination with tritiated glucose. The OGTT-derived indexes of muscle and hepatic insulin sensitivity were compared with hepatic and muscle insulin sensitivity, which was directly measured with the insulin clamp, by correlation analysis. RESULTS:--The product of total area under curve (AUC) for glucose and insulin during the first 30 min of the OGTT (glucose₀₋₃₀AUC x insulin₀₋₃₀AUC) strongly correlated with the hepatic insulin resistance index (fasting plasma insulin x basal endogenous glucose production) (r = 0.64, P < 0.0001). The rate of decay of plasma glucose concentration from its peak value to its nadir during the OGTT divided by the mean plasma insulin concentration (dG/dt divide sign I) strongly correlated with muscle insulin sensitivity measured with the insulin clamp (P = 0.78, P < 0.0001). CONCLUSIONS:--Novel estimates for hepatic and muscle insulin resistance from OGTT data are presented for quantitation of insulin sensitivity in nondiabetic subjects.
OBJECTIVE: Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 ...diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance. RESEARCH DESIGN AND METHODS: Forty-one subjects (8 lean with normal glucose tolerance NGT, 9 obese with NGT, 12 with impaired fasting glucose IFG/impaired glucose tolerance IGT, and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m² per min) combined with 3-³H glucose infusion. RESULTS: Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = -0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose r = 0.312, P = 0.05, 2-h plasma glucose r = 0.414, P = 0.01, and A1C r = 0.325, P = 0.04). CONCLUSIONS: Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.
What Is the Best Predictor of Future Type 2 Diabetes?
Muhammad A. Abdul-Ghani , MD, PHD ,
Ken Williams , MS ,
Ralph A. DeFronzo , MD and
Michael Stern , MD
From the Divisions of Diabetes and Clinical ...Epidemiology, University of Texas Health Science Center at San Antonio, San Antonio,
Texas
Address correspondence and reprint requests to Muhammad A. Abdul-Ghani, MD, PhD, Diabetes Division, University of Texas Health
Science Center, 7703 Floyd Curl Dr., MS 7886, San Antonio, TX 78229. E-mail: albarado{at}uthscsa.edu
Abstract
OBJECTIVE —We sought to assess insulin secretion/insulin resistance index in predicting the risk for future type 2 diabetes
RESEARCH DESIGN AND METHODS —A total of 1,551 nondiabetic subjects from the San Antonio Heart Study received an oral glucose tolerance test (OGTT) with
measurement of plasma glucose and insulin concentrations at 0, 30, 60, and 120 min at baseline and after 7–8 years of follow-up.
Insulin secretion/insulin resistance index was calculated as the product of Matsuda index and ΔI 0–30 /ΔG 0–30 or ΔI 0–120 /ΔG 0–120 . The discriminatory power of various prediction models for development of type 2 diabetes was tested with the area under
the receiver-operating characteristic (ROC) curve.
RESULTS —Insulin secretion/insulin resistance index (0- to 30- and 0- to 120-min time periods) had the greatest areas under the ROC
curve (0.85 and 0.86, respectively), which were significantly greater than the 2-h plasma glucose concentration during the
OGTT or the San Antonio Diabetes Prediction Model (SADPM) ( P < 0.001 and P < 0.0001, respectively). A model based on the combination of the SADPM and a modified version of the insulin secretion/insulin
resistance index or 1-h plasma glucose concentration had equal power to predict the risk for future type 2 diabetes compared
with the insulin secretion/insulin resistance index.
CONCLUSIONS —The insulin secretion/insulin resistance index is useful as a predictor of future development of type 2 diabetes. A model
based on the combination of the SADPM and either a modified version of the insulin secretion/insulin resistance index or 1-h
plasma glucose concentration can equally predict future type 2 diabetes.
IGT, impaired glucose tolerance
NGT, normal glucose tolerance
OGTT, oral glucose tolerance test
ROC, receiver-operating characteristic
SADPM, San Antonio Diabetes Prediction Model
Footnotes
Published ahead of print at http://care.diabetesjournals.org on 23 March 2007. DOI: 10.2337/dc06-1331.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted March 9, 2007.
Received June 26, 2006.
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