Hypoglycemia: Still The Limiting Factor in the Glycemic Management of Diabetes

Cryer, Philip E.

doi:10.4158/ep.14.6.750

Cited by 218 publications

(205 citation statements)

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“…Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11)(12)(13)(14). Therefore, despite the profound diabetes-improving and life-saving effects of insulin-based therapies, they do not restore metabolic homeostasis and may even lead to serious side effects.…”

mentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

222

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Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulindeficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.brain | leptin monotherapy | glucose homeostasis | glucagon suppression A ccording to the Juvenile Diabetes Research Foundation, type 1 diabetes (T1D) afflicts 1-3 million people in the United States alone. Regrettably, for reasons yet to be understood, the incidence of T1D has been increasing at an alarming annual rate of ∼3%, thus indicating that the number of patients with T1D is predicted to rise significantly in the future (1). T1D occurs as a consequence of pancreatic β-cell destruction leading to insulin deficiency, a defect that causes hyperglycemia, hyperglucagonemia, cachexia, ketoacidosis, and other abnormalities (2, 3). T1D is a deadly condition if not treated. Current life-saving interventions include daily insulin administration; insulin therapy reduces hyperglycemia, glycosylated hemoglobin, and cachexia and prevents or delays some T1D-associated morbidities (3, 4). However, even with insulin therapy, T1D secondary complications include debilitating and long-lasting conditions, such as heart disease, neuropathy, and hypertension (5-7). Moreover, probably because of insulin's lipogenic and cholesterologenic actions, longterm insulin treatment is suspected to underlie the increased ectopic lipid deposition (i.e., in nonadipose tissues) (8) and incidence of coronary artery disease (>90% after the age of 55 y) (9, 10) seen in patients with T1D. Furthermore, in part attributable to insulin's potent, fast-acting, glycemia-lowering effects, intensive insulin therapy significantly increases the risk for hypoglycemia, an event that is disabling and can even be fatal (3,(11...

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mentioning

confidence: 99%

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Fujikawa

Chuang

Sakata

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

182

222

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“…Thus, real-time CGM use minimizes low blood glucose exposure and may reduce the risk of developing hypoglycemia unawareness. 18 There are also some limitations of the study. The inpatient setting enabled reliable blood glucose measurement at a sufficient frequency to demonstrate the ability of CGM to avoid biochemical hypoglycemia, but it also limited the duration of the study.…”

Section: Discussionmentioning

confidence: 99%

The Impact of Continuous Glucose Monitoring on Low Interstitial Glucose Values and Low Blood Glucose Values Assessed by Point-of-care Blood Glucose Meters

Hermanns

Schumann

Kulzer

et al. 2014

J Diabetes Sci Technol

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Continuous glucose monitoring (CGM) is a promising tool supporting people with diabetes in improving glycemic control without increasing the risk of hypoglycemia. Recent meta-analysis suggests that CGM use reduces the duration of hypoglycemic and hyperglycemic phases, whereas the time spent in euglycemia is prolonged.1,2 Thus, CGM promises to facilitate the avoidance of hypoglycemic glucose levels while improving overall glycemic control. The beneficial impact of CGM on avoiding high glucose values was not only demonstrated by glucose measurements of the CGM system itself, but also by the reduction of HbA1c.3,4 This is corroborated by recent studies and meta-analyses of studies that used early generation devices showing that overall glycemic control could be improved. 2,[5][6][7] In the meta-analysis, reductions between 0.2 and 0.7 A1c percentage points were observed due to the use of CGM. 1,2 Furthermore there are also meta-analytic findings that the exposure to hypoglycemia could be reduced.1 However, the avoidance of severe hypoglycemia as a clinical endpoint by means of CGM could not be demonstrated.1,2 In contrast to the outcomes concerning the reduction of hyperglycemia, which could be corroborated by independent measures (eg, A1c) or episodes of ketoacidosis, 1,2 the results regarding minimizing hypoglycemia relied only on the CGM measurements themselves. This is problematic since it is known that the results of CGM of early generation CGM systems in the hypoglycemic range are less concordant with laboratory or point of care (POC) measurements than the results of CGM in the eu-or hyperglycemic range. In the low glycemic range, 524105D STXXX10.1177/1932296814524105Journal of Diabetes Science and TechnologyHermanns et al AbstractIn a randomized crossover trial the impact of continuous glucose monitoring (CGM) was tested on the occurrence of low blood glucose values measured by point of care (POC) measurement and on low glucose values measured by CGM in the interstitial fluid. A total of 41 type 1 diabetic patients (age 42.0 ± 11.4 years, diabetes duration 15.3 ± 10.1 years, A1c 8.2 ± 1.4%) used a CGM system (Dexcom SEVEN PLUS system) twice. In first study phase (CGM blind), patients were blind regarding the CGM current glucose levels and were not alerted when critical glucose values were reached. In the second phase (CGM real time), patients had access to current glucose levels and were alerted if critical glucose values were reached. During CGM real time the proportion of hypoglycemic POC blood glucose values were significantly reduced (7.5 ± 5.6% vs 10.1 ± 7.5%; P = .04), whereas the proportion of euglycemic blood glucose values were significantly enhanced (73.7 ± 18.3% vs 68.3 ± 12.1%; P = .01). The duration of low glucose periods in the interstitial fluid was significantly lower in the CGM real time phase (125 ± 89 vs 181 ± 125 minutes per day; P = .005). The time until a low blood glucose was detected by POC measurement was shortened by 33.2 ± 76.1 minutes (P = .03). The study demonstrated that CGM is ...

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“…The intensive insulin therapy required to achieve the tight glycemic control, based on the injection of basal and bolus insulin to reproduce its physiological secretion, has as counteraction an increase in the risk of significant and severe hypoglycemia with all their consequences. Therefore, hypoglycemia is considered as one of the major limiting factors in achieving tight glycemic control in T1DM (Cryer (2008)). With the inability of conventional therapy to achieve satisfactory glycemic control, and the development in continuous glucose monitoring (CGM) systems and the increasing use of insulin pumps, the idea of developing an artificial pancreas is viewed as the ideal solution for glycemic control in T1DM (Bequette (2005); Hovorka et al (2006); Kumareswaran et al (2009)).…”

Section: Introductionmentioning

confidence: 99%

Hypoglycemia Prevention in Closed-Loop Artificial Pancreas for Patients with Type 1 Diabetes

Abu-Rmileh¹,

Garcia-Gabin²

2011

Diabetes - Damages and Treatments

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Hypoglycemia: Still The Limiting Factor in the Glycemic Management of Diabetes

Cited by 218 publications

References 50 publications

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice

The Impact of Continuous Glucose Monitoring on Low Interstitial Glucose Values and Low Blood Glucose Values Assessed by Point-of-care Blood Glucose Meters

Hypoglycemia Prevention in Closed-Loop Artificial Pancreas for Patients with Type 1 Diabetes

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