A fully implantable device for intraperitoneal drug delivery refilled by ingestible capsules

Creating fully implantable robots that replace or restore physiological processes is a great challenge in medical robotics. Restoring blood glucose homeostasis in patients with type 1 diabetes is particularly interesting in this sense. Intraperitoneal insulin delivery could revolutionize type 1 diabetes treatment. At present, the intraperitoneal route is little used because it relies on accessing ports connecting intraperitoneal catheters to external reservoirs. Drug-loaded pills transported across the digestive system to refill an implantable reservoir in a minimally invasive fashion could open new possibilities in intraperitoneal delivery. Here, we describe PILLSID (PILl-refiLled implanted System for Intraperitoneal Delivery), a fully implantable robotic device refillable through ingestible magnetic pills carrying drugs. Once refilled, the device acts as a programmable microinfusion system for precise intraperitoneal delivery. The robotic device is grounded on a combination of magnetic switchable components, miniaturized mechatronic elements, a wireless powering system, and a control unit to implement the refilling and control the infusion processes. In this study, we describe the PILLSID prototyping. The device key blocks are validated as single components and within the integrated device at the preclinical level. We demonstrate that the refilling mechanism works efficiently in vivo and that the blood glucose level can be safely regulated in diabetic swine. The device weights 165 grams and is 78 millimeters by 63 millimeters by 35 millimeters, comparable with commercial implantable devices yet overcoming the urgent critical issues related to reservoir refilling and powering.

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Early hyperglycemia following alloxan administration in vivo is not associated with altered hepatic mitochondrial function: acceptable model for type 1 diabetes?

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y11-044 ◽

2011 ◽

Vol 89 (7) ◽

pp. 477-484 ◽

Cited By ~ 5

Author(s):

Dairo A. Rendon ◽

Jose A. Alvarez-Bustamante

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Mitochondrial Dysfunction ◽

Glucose Concentration ◽

Alloxan Diabetes ◽

Blood Glucose Concentration ◽

Diabetic State ◽

Acceptable Model

Alloxan and oxidative stress, which have been detected in livers of laboratory animals shortly after in vivo alloxan administration, cause in vitro mitochondrial dysfunction, thus questioning alloxan diabetes as an acceptable model for type 1 diabetes, a model that cannot legitimately be used to investigate mitochondrial metabolism in a diabetic state. In the current study, the blood glucose concentration increased in the drug-treated group of Sprague–Dawley rats (compared with the placebo group) 45 or 60 min after alloxan treatment, whereas at 30 min the blood glucose concentration was unchanged. State 4, state 3, respiratory control, efficiency of oxidative phosphorylation, and mitochondrial ATP synthase activity, assayed using glutamate plus malate, pyruvate plus malate, or succinate as a substrate, were not negatively altered during the entire study. These results indicated that early increases of blood glucose concentration, after in vivo alloxan administration, did not lead to liver mitochondrial dysfunction, suggesting that alloxan diabetes can be used for the study of liver mitochondrial respiration in a diabetic state.

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Systemic Delivery of TNF-Related Apoptosis-Inducing Ligand (TRAIL) Elevates Levels of Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) and Prevents Type 1 Diabetes in Nonobese Diabetic Mice

Endocrinology ◽

10.1210/en.2009-0478 ◽

2010 ◽

Vol 151 (12) ◽

pp. 5638-5646 ◽

Cited By ~ 15

Author(s):

Soojeong Kang ◽

Eun-Jin Park ◽

Yeonsoo Joe ◽

Eunhui Seo ◽

Mi-Kyoung Park ◽

...

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Gelatin Zymography ◽

Nod Mice ◽

Tissue Inhibitor Of Metalloproteinase ◽

Tissue Inhibitor ◽

Nonobese Diabetic ◽

Induced Apoptosis

Recent studies have demonstrated that TNF-related apoptosis-inducing ligand (TRAIL) is a modulator of the immune response. The relation between TRAIL and type 1 diabetes (T1D) as an autoimmune inflammatory disease in vivo is relatively unknown. To explore the potential role of TRAIL in the development of T1D, we examined its in vivo effects in nonobese diabetic (NOD) mice. NOD mice at 7 wk of age were iv injected with an adenovirus carrying either human TRAIL (Ad.hTRAIL) or β-galactosidase genes. Blood glucose was monitored weekly, and the expression of hTRAIL was evaluated in plasma and liver of mice. To investigate whether hTRAIL elicits its effect through the induction of tissue inhibitor of metalloproteinase-1 (TIMP-1), we examined the concentration of plasma TIMP-1 by ELISA and the inhibition of matrix metalloproteinase (MMP) by gelatin zymography. Here, we show that Ad.hTRAIL-transduced mice had significantly reduced blood glucose levels and markedly increased production of TIMP-1 compared with control β-galactosidase animals. Pancreatic tissue isolated from Ad.hTRAIL-treated NOD mice showed reduced MMP activities associated with significantly improved insulitis. In addition, TIMP-1 in vitro suppressed cytokine-induced apoptosis in insulin-producing INS-1 cells. These results indicate that T1D can be prevented by TRAIL overexpression through enhancement of TIMP-1 function. Elevated TIMP-1 production inhibits the activity of MMPs, which may contribute to suppress the transmigration of diabetogenic T cells into the pancreatic islets and protects pancreatic β-cells from cytokine-induced apoptosis. Therefore, TRAIL and TIMP-1 induction may be potential targets to prevent development of T1D.

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Blood glucose regulation and control of insulin and glucagon infusion using single model predictive control for type 1 diabetes mellitus

IET Systems Biology ◽

10.1049/iet-syb.2019.0101 ◽

2020 ◽

Vol 14 (3) ◽

pp. 133-146 ◽

Cited By ~ 2

Author(s):

Cifha Crecil Dias ◽

Surekha Kamath ◽

Sudha Vidyasagar

Keyword(s):

Diabetes Mellitus ◽

Type 1 Diabetes ◽

Blood Glucose ◽

Type 1 Diabetes Mellitus ◽

Predictive Control ◽

Glucose Regulation ◽

Single Model ◽

Blood Glucose Regulation ◽

And Control

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Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

eLife ◽

10.7554/elife.72919 ◽

2021 ◽

Vol 10 ◽

Author(s):

Angela Kim ◽

Jakob G Knudsen ◽

Joseph C Madara ◽

Anna Benrick ◽

Thomas Hill ◽

...

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Arginine Vasopressin ◽

Glucagon Secretion ◽

Glucagon Release ◽

Alpha Cells ◽

Major Barrier ◽

Circulating Levels

Insulin-induced hypoglycemia is a major barrier to the treatment of type-1 diabetes (T1D). Accordingly, it is important that we understand the mechanisms regulating the circulating levels of glucagon - the body's principal blood glucose-elevating hormone which is secreted from alpha-cells of the pancreatic islets. Varying glucose over the range of concentrations that occur physiologically between the fed and fuel-deprived states (from 8 to 4 mM) has no significant effect on glucagon secretion in the perfused mouse pancreas or in isolated mouse islets (in vitro) and yet associates with dramatic changes in plasma glucagon in vivo. The identity of the systemic factor(s) that stimulates glucagon secretion remains unknown. Here, we show that arginine-vasopressin (AVP), secreted from the posterior pituitary, stimulates glucagon secretion. Glucagon-secreting alpha-cells express high levels of the vasopressin 1b receptor gene (Avpr1b). Activation of AVP neurons in vivo increased circulating copeptin (the C-terminal segment of the AVP precursor peptide, a stable surrogate marker of AVP) and increased blood glucose; effects blocked by pharmacological antagonism of either the glucagon receptor or vasopressin 1b receptor. AVP also mediates the stimulatory effects of hypoglycemia produced by exogenous insulin and 2-deoxy-D-glucose on glucagon secretion. We show that the A1/C1 neurons of the medulla oblongata drive AVP neuron activation in response to insulin-induced hypoglycemia. Exogenous injection of AVP in vivo increased cytoplasmic Ca2+ in alpha-cells (implanted into the anterior chamber of the eye) and glucagon release. Hypoglycemia also increases circulating levels of AVP in humans and this hormone stimulates glucagon secretion from isolated human islets. In patients with T1D, hypoglycemia failed to increase both plasma copeptin and glucagon levels. These findings suggest that AVP is a physiological systemic regulator of glucagon secretion and that this mechanism becomes impaired in T1D.

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Materializing Datafied Body Doubles: Insulin Pumps, Blood Glucose Testing, and the Production of Usable Bodies

Catalyst Feminism Theory Technoscience ◽

10.28968/cftt.v5i1.29613 ◽

2019 ◽

Vol 5 (1) ◽

pp. 1-26

Author(s):

Stephen Horrocks

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Insulin Pump ◽

The Body ◽

Glucose Testing ◽

Physiological Processes ◽

Blood Glucose Testing ◽

Continued Use ◽

Data Collections

The network of devices involved in insulin pump treatment reads and quantifies the physiological processes of Type 1 Diabetes as it performs life-sustaining functions inside and upon users’ bodies. Together, these devices gather that information to produce what I call Datafied Body Doubles: numerical stand-ins for the body that recreate them as both usable and controllable for pump users and their physicians. By establishing and normalizing a system of quantification through blood glucose testing and temporally mapping body-readings into data collections, these Datafied Body Doubles fundamentally alter the conceptual and material experience of living with Diabetes. As medically-compelled users, people with Type 1 Diabetes participate in their own datafication through their continued use of those devices—a choice which is not much of a choice at all—but their bodies are re-created and used to drive their participation in those very techno-medicalized treatments nevertheless.

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Brain Glycogen Content and Metabolism in Subjects with Type 1 Diabetes and Hypoglycemia Unawareness

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.138 ◽

2011 ◽

Vol 32 (2) ◽

pp. 256-263 ◽

Cited By ~ 40

Author(s):

Gülin Öz ◽

Nolawit Tesfaye ◽

Anjali Kumar ◽

Dinesh K Deelchand ◽

Lynn E Eberly ◽

...

Keyword(s):

Type 1 Diabetes ◽

Blood Glucose ◽

Glycogen Content ◽

Blood Glucose Concentration ◽

Occipital Lobe ◽

Resonance Spectroscopy ◽

Hypoglycemia Unawareness ◽

Brain Glycogen

Supercompensated brain glycogen may contribute to the development of hypoglycemia unawareness in patients with type 1 diabetes by providing energy for the brain during periods of hypoglycemia. Our goal was to determine if brain glycogen content is elevated in patients with type 1 diabetes and hypoglycemia unawareness. We used in vivo13C nuclear magnetic resonance spectroscopy in conjunction with [1-13C]glucose administration in five patients with type 1 diabetes and hypoglycemia unawareness and five age-, gender-, and body mass index-matched healthy volunteers to measure brain glycogen content and metabolism. Glucose and insulin were administered intravenously over ∼51 hours at a rate titrated to maintain a blood glucose concentration of 7 mmol/L. 13C-glycogen levels in the occipital lobe were measured at ∼5, 8, 13, 23, 32, 37, and 50 hours, during label wash-in and wash-out. Newly synthesized glycogen levels were higher in controls than in patients ( P<0.0001) for matched average blood glucose and insulin levels, which may be due to higher brain glycogen content or faster turnover in controls. Metabolic modeling indicated lower brain glycogen content in patients than in controls ( P=0.07), implying that glycogen supercompensation does not contribute to the development of hypoglycemia unawareness in humans with type 1 diabetes.

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