Introduction:

Type II diabetes or non-insulin-dependnet diabets mellitus accounts for over 90% of the diagnosed cases of diabetes and affects more than 16 million people in the US and some 200 million people around the world. Type II diabetes is a metabolic disease characterized by hyperglycemia and is a worldwide major public health care problem, affecting some 194 million worldwide.

Pathology:

Decreased Insulin Receptors/Insulin Resistance: Contrasting with type I diabetes, type II diabetic individuals have normal or even greatly elevated insulin levels. Their symptoms arise from an apparent paucity of insulin receptors on normally insulin responsive cells. It has been hypothesized that the increased insulin production resulting from overeating, consequent obesity, eventually, suppresses the synthesis of insulin receptor.  In Type II diabetic people, either the body does not produce enough insulin or the cells ignore insulin. Thus, instead of being absorbed by the cells, the glucose remains in blood leading to hyperglycemia.

Studies of genetically predisposed individuals have indicated that insulin resistance in the muscle is the primary or initating defect leading to the ultimate development of T2D. Thus, skeletal muscle is a mian target to fight against development of insulin-resistance in prediabetic state or during early stage of T2D. (Magnan, “Regnerating islet-derived protein 3 alpha: a promising therapy for diabetes. Preliminary data in rodents and in humans” Heliyon 8 (2022).

Inflammation: Type 2 diabetes is associated with a high cardiovascular risk, which is even increased if renal damage is superimposed. Peripheral blood mononuclear cells (PBMCs) and pro-inflammatory cytokines are key factors linking type 2 diabetes and atherosclerosis. Navarro (Nephrol Dial Transplant (2008) 23: 919-926) discloses disclsoses isolating PBMCs from diabetic patients with normal renal function and different stages of diabetic nephropathy and showing a relationship between inflammatory activation of PBMCs by enhanced mRNA expression of TNF-alpha and IL-6.

Causes of Diabetes

Obesity is the most important nutritional disorder in the western world, with the estimates of its prevalence ranging from 30-50% within the middle aged population. It is usually defined as a body weight more than 20% in excess of the ideal body weight. Obesity is associated with an increased risk for cardiovascular diseases, diabetes, stroke, muscular dystruphy and infertility. In particular, obesity can evolve to type II diabetes in successvie phases.

Obesity is defined by the WHO as an abnormal or excessive fat accumulation that may impair health. It is defined by body mass index (BMI), weight in kilograms divided by the square of height in meters, in adults over 30 kg/m2. (Chavda, Molecules 2022, 27, 4315).

The genetic basis for obesity and diabetes has gradually progressed. Zhang cloned the mouse obesity (ob) gene and its human homologue in 1994 (Zhang, Nature, 372 (2994) 425-432). Mutation in ob leads to symptoms of obesity. Several other single gene mutations resulting in obesity in mice have been identified. For example, the yellow mutation at the agouti locus has been found to cause a pleiotropic syndrome which causes moderate adult onset obesity, a yellow coat color, and a high incidence of tumor formation (Herberg and Coleman (1977), Metabolism 26: 59) and an abnormal anatomic districution of body fat (Coleman (1973) Diabetologia 14: 141-148).

The most widely used method to gauge obesity is the body mass index BMI which is equal to weight-height2in kg-m2.  A BMI of 30 is most comonly used as a thereshold for obesity. A BMI between 25’30 should be viewed as medically significant.

Complications/Symptoms of Diabetes:

see WebMD (discusses diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy).

Prevention/Treatment Strategies:

Treatment of T2D includes lifestyle changes such as diet, exercise, and mutraceuticals, as well as administration of medications such as metformin. Conventionally, two sorts of therapeutic agents have been used for the treatment of T2D. (Chavda, Molecules 2022, 27, 4315).

The obesity market is currently dominated by Novo Nordisk and Eli Lilly. Several companies including Pfizer, Roche, Viking Therapeutics and Rivus Pharmaceuticals are also developing obesity therapeutics. Some leverage the GLP-1 pathway, while others commit to different mechanisms, including amylin analogs and mitochondrial uncoupling. Other players in the space include Veru Pharmaceuticals, Regneron, Altimmune, Amgen and Amylyx.

Currenlty, various pharmacological approaches are avialbe for treating hyperglycemia and subsequently, T2DM. These may be groups into the following classes:

Insulin secretogogues: including sulphony-ureas (e.g., glipizide, glimepiride, glyburide), meglitinides (e.g., nateglidine, repaglinide), dipeptidyl peptidase IV 9DDP-IV inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin), and glucagon-like peptide-1 receptor (GLP-1R) agonists (e.g., liragludie, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide) which enahce secretion of insulin by acting on the pancreatic beta-cells. Suponyl-ureas adn meglitinides have limited effiacy and tolerability, cause weight gain and often induce hypoglycemia. DPP-IV inhibitors have limited efficacy. Marekted GLP-1R agonists are peptides adminsitered by subcutaneous injection. Liraglutide is additionally prroved for teh treatment of obesity.

Biguanides (e.g., metformin) are thought to act primarily by decreasing heaptic glucose production. Biguanides often casue gastrointestinal disturbances and lactin acidsosis, further limited their use.

Inhibitors of alpha-glucosiase (e.g., acarbose) decreases intestinal glucose absorption. These agents often cause gastrointestinal disturbances.

Thiazolidinediones (e.g. pioglitazone, rosiglitazone) act on a specific receptor (peroxisome proliferator-activated receptor-hamma) in the liver, musle and fat tiessues. They regualted lipid metabolism subsequently enhancing the response of these tissues to the actions of insulin. Frequent use of these drugs may lead to weight gain and may induce edmea and anemia.

Insulin is used in more severe cases, either alone or in combination with the above agents, and frequent use may also lead to weight gain and carries a risk of hyoplycemia.

Sodium-glucose linked transporter cotransporter 2 (SGLT2) inhibitors (e.g., dapagliflozin, empagliflozin, canaglifloxin, ertugliflozin) inhbit reabsorption of glucose in the kidneys adn thereby lwoer glucose levesl int he blood. This emerging class of drugs may be assocaited with ketoacidosis and urinary tract infections.

Lectins:

–Regenerating islet-derived protein 3alpha (Reg3alpha, Reg3A) (hepatocarcinoma-intestinal-pancreas/pancreatitis-associated protein (HIP/PAP)): is a 16 kDA type C lectin protein with a single carbohydrate binding domain. Reg3alpha is also secreted and carries out its biological activites in an autocrine and paracine manner. It could also act in an endocrine manner since it is also detected in the bloodstream. This protein has been shown to drive tissue repair and regeneration as well as protection against oxidative sttress and cell death in the liver, pacreas and intestine. It also promotes motor neuron axonal survival and guidance and Schwann cell proliferation. It shows anti-inflammatory activites and yeilds antibacterial activiteis in the digestive tract. The prtoein shows an intrinsic ROS cavenger actiity targeted on the extra-cellular matrix in the context of inflammation. Administration of Reg3alpha has been shown to control glucose homeostasis and could potentially be a new target of interest in the treatment of type 2 daibetes. In this respect, recombinant human Reg3alpha prtoein was adminsitered to insulin resistant mice fed a high fat diet. An increase in insulin sensitivity during an oral glucose tolerance test and decrease in teh pro-inflammtory cytokine C-X-C Motif Chemokine Ligand 5 (CXCL5) was evidenced. There was also an increase in glucose uptake in the skelatal musle. (Magnan, “Regnerating islet-derived protein 3 alpha: a promising therapy for diabetes. Preliminary data in rodents and in humans” Heliyon 8 (2022).

Biomarkers Related to Diabetes:

Lower Your A1C levels:

When you have diabetes you should check your blood sugar regularly. Also recommended is to check A1C levels, which measures the amount of sugar which attaches to the protein hemaglobin. In general, A1C levels should be below 7%. When you take steps ot lower your A1C, you can reduce complications such as nerve damage, eye problems and heart disease.

Incretins (“Incretin homones):

Incretins stimulate beta cells to release insulin and were discovered in the early 1972. These products are secreted in the intestine, affecting the functioning of beta cells. The most commonly known incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent inulinotropic polypeptide (GIP). GLP-1 and GIP are peptide hormones that are secreted with the benefit of utilizing cells from intestines called enteroendocrine cells in reaction to the consumption of nutrients, and they have an important function in posprandial metabolism. With the identification of glucose equilibrium, their most favorable condition, the incretin effect, begins to improve the glucose-stimulated release of insulin from the pancreas. GIP is considered to be the essential incretin hormone accounting for this effect.( Chavda, Molecules 2022, 27, 4315)

GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to simulate insulin secretyion in a physiological adn glucose-dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta-cells. In non-clinal experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insuline secretion and by promoting beta-cell neogensis. In a healthy individual, GLP-1 plays an important role regualting post-prandial blood glucose leves by sitmulating glucose-dependet insulin secretion by the pancrease resutling in increased glucose absorption in the periphery. GLP-1 also suppresses glucoan secretion leading to reduced heaptic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal post-prandial rise in GLP-1 is absent or reduced. (WO 2018/109607)

In 2019, the FDA approved Novo’s Rybelsus for the first oral GLP-1 for type 2 diabetes. Considered by many to be the next frontier in obesity treatment, oral medicines are under development by a number of companies, including Novo, whose amycretin is in phase I trials  and Lilly, which has a Phase III trial underway for orforglipron. Brazilian owned multinational company Eurofarma also has a Phase III study under way for its oral candidate sibutramine/topiramate XR. Phizer recently accouned that it would move forward with a modified release formulation of its candidate danuglipron and in December 2023, San Francisco-based Structure Therapeutics accouned postive resutls form a Phase IIa trail of its weight-loss pill GSBR-1290. (clinicaspace, “Obesity and Diabetes Markets Explode”, 2024).

Glucagon-like peptide 1 (GLP-1) Agonists:

GLP-1 receptor agonists make up a class of medications used for the treatment of type 2 diabetes and obesity. The first GLP-1 receptor agonist to reive FDA approval was exenatide in 2005 and the FDA subsequently approved several other drugs with the same mechanisms of action. More than 15 years latter, these products remain costly with monthly net prices rising to more than $600 in 2017. The mediuan annual out of pocket cost in Medicare Part D exceeded $15000 in 2019. Manufacturers earned mroe than 10 billion on GLP-1 agonists in the US alone in 2021. (JAMA, “Patents and Regulatory Exlusivities on GLP-1 Receptor Agonists”, 2023, 330(7)).

Other FDA approved GLP-1 receptor agonstis include Victoza (Liaglutide), Bydureon (Exenatide), Saenda (Liraglutide), Adlyxin (Lixisensatide), Xultophy (liraglutide), Soliqua (lixisenatide)and Ozempic, Rybelsus (Semaglutide).

Most marketed GLP-1 receptor agonists are drug-device combinations with active ingredients sold together with their subcutaneous inector pens. Device patents expiring later than other patents may force generic firms to either wait until these patents expire before market entry or undertake lenghty and costly patent challenges. (JAMA, “Patents and Regulatory Exlusivities on GLP-1 Receptor Agonists”, 2023, 330(7))

GLP-1 is a hormone that is screted by the small intestine, generally promotes the biosynthesis and secretion of insultin, inhibits the secretion of glucagon. (Song, WO 2008/082274)

Song, WO 2008/082274 discloses an insulinotropic peptide for promoting the syntehsis and expression of insulin such as GLP-1 conjugate haivng improved in vivo duration and stability which includes an insulinotropic peptide, a non-peptide polymer and an immunoglobulin Fc region which are covalently linked to each other. If the insulinotropic peptide to be coupled at a site other than the N-temrinus, a reactive thiolgroup can be introduced to the site of amino acid resiude to be modified in the native amino acid sequence to form a covalent bond using a maleimide linker at hte non-peptidyl polymer. Alternatively, a reactive amine group can be introduced to the site of amino acid resiude to form a covalent bond using an aldehyde linker at the non-eptidyl polymer.

–Exenatide (Gyetta, AstraZeneca):  is a GLP-1 receptor agonist released from the gut and acts to increase glucose-dependent insulin secretion from pancreatic beta cells, suppress glucagon secretion, delay gastric emptying, and reduce food intake. The binding of the drug to pancreatic GLP-1 receptors mediates these actions. Administration of exenatide has shown restoration in the insulin response that is usually defective in type 2 diabetic patients. Researchers also observed the prolonged release of insulin in response to elevated glucose levels was also observed in patients treated with exenatide. Treatment with exenatide leads to the decreased release of glucagon during hyperglycemic periods, which reduces hepatic glucose output as well as decreases insulin demand. Delayed gastric emptying decreases the rate at which glucose arrives in the bloodstream. Exenatide is available as an immediate-release solution and extended-release suspension for subcutaneous administration. The administration of these injections should be in the thigh, abdomen, or upper arm. Additionally, patients should receive instruction to use a different injection site for each dose to prevent infection.

Exenatide is made by Amylin Pharmaceuticals and commercialized by AstraZeneca. Exenatide was approved by the FDA in April 2005, for people whose diabetes is not well controlled on other oral medications.

–Semaglutide (Ozempic, Novo Nordisk): is a GLP-1 RA and widely used. An oral form of Simaglutide to be adminsitered once a wekk is also available. (Chavda, Molecules 2022, 27, 4315)

–Tirzepaptide (Mounjaro™): is comparable to GLP-1 agonists, as it is a dual GIP/GLP-1 agonist. The FDA has approved tirzepatide under the brand name Mounjaro, which has become a revolutionary agent for the management and treatment of T2D and achieving weight loss. The most common side effects assocaited with tirzepatide are related to gastrointestinal tract like nausea, vomiting and diarrhea. Tirzepatide is a single molecule that combines dual agonism of glucose-dependent insulain tropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. Tirzepatide binds to GIP and GLP-1 receptors with high affinity that is similar to that of native GIP and about 5 fold weaker than that of native GLP-1. Native GIP and GLP-1 are incretin hormones that stimulate insulin secretion and decrease glocagon secretion. GIP also plays a role in nutrient and energy metabolism, while GLP-1 also delays gastric emptying, suppresses appetide and improved satiety. Eli Lilly is developing irzepatide for the treatment of type 2 diabetes mellitus (T2DM), obesity, cardiovscular disorders in T2DM, hert failure, non-alcoholic steatohepatitis, obstructive sleep apnoea and for reducing mortaility/morbidity in obsity. (Syed Druges (2022) 82: 121-1220).

Tirzepatide is a synthetic linear peptide molecule containing 39 amino acids. Residues derive form GLP-1, GIP and semaglutide and few residues are unique. The strucure is based on the native GIP sequence and includes C20 fatty diacid moeity (eicosanedionic acid) linke via hydrophilic linkesconnecte to lysine reisudes at C20 position. The peptide sequence contains two non-coded amino acid resiudes at position 2 and 13 which are responsible for its long half-life and high affinity to albumin. The main critical improvements are modificaiton of residues in the peptide backbone to obtain GIP receptor activating activity. Tirzepatide is the first agent that functions as a dual agonist for the two main human GLP-1 and GIP incretins. It has impressive glycemic efficacy. Moreover, it is the first effective drug to have demonstrated notable body weight loss in a phase 3 study in patients with T2D. Trizepatide has significanlty better therapetuic efficacy than current drugs. It is also superior to semaglutide and insulin degludec. Phase 1 clinicl trails which lasted for 4 weeks, followed by 4 weeks of safety investigation, for tirzepatide showed a remarkable statistical decrease in HbA1c, and postprandial glucose levels were also found to be diminished. A 26 week long phase 2 clinical trials, which also included a dulaglutide group, showed better efficacy over dulaglutide. It also contributed to reduction of weight and decreased appetide in the subjects. In the SURPASS-1 phase 3 clinical trails, which included six countries worldwide, patietns who had ongoing treatment with SLGT2 inhibitors were included. Soytel with or without metformin, a dose-dependent impact on HbA1c and weight loss was observed, which was larger than that of the slective GLP-1RA dulaglutide. Meanwhile, in a 12-week phase 2 trial with moderate dose escalation regimens, gastrointestinal tolerability improved when starting with a lower dose and slowly increaseing to the highest effective doses. Other additional effect of tirzepatide were noted to lowering the concentrations of very low-density lipoproteins and triglycerides, in addition to a reduction in blood pressure, as well as an elevation of high density lipoprotein concentraiton. The adverse events most commonly reported were nausea, vomiting and diarrhea, which were mild to moderate and occurred mostly during the dose-escalation period.   (Chavda, Molecules 2022, 27, 4315) Besoe most common adverse events were gastrointestinal events, including nausea, vomiting and diarrhea. Most of these events were mild to moderate. n (US 2020/0023040) disclsoes administration of tirzepatide from a lower starting escalation dose to a higher maintenance dose.

Metformin: is an FDA approved drug to treat Type 2 diabetes. It is an oral medication approved for people as young as 10. While Mounjaro provides better blood glucose control and more potential weight loss than metformin, metformin is often more cost effective for many people. Metformin has been a mainstay when it comes to treating type 2 diabetes for decades. Metformin remains the go to choice for many providers when prescribing a Type 2 diabetes medication because it works and is cost effective. Metformin effectively lowers hemoglobin A1C (HbA1C or A1C). Your A1C represents your average blood glucose over 3 months.

Metformin is a biguanide. Similarly to Mounjaro, it lowers the amount of glucose the liver makes. But Metformin does not increase pancreas release of insulin. Instead, it makes the body more sensitive to the insulin one makes naturally. It also lowers the amount of glucose one absorbed from the food. Because Mounjaro and metformin work in two different ways, they can be combined for additional blood glucose improvement.

–Metformin and Herbal Formula:

Metformin and a Chinese herbal formula may ameliorate type 2 diabetes with hyperlipidemia via enriching beneficial bacteria, such as Blautia and Faecalibacterium. The herbs used were Rhizona Anemarrhenae, Momordica charantia, Coptis chinensis, Ale vera and red yeast rice (Zhao, “Structural alteration of gut microbiota during the amelioration of human type 2 diabetes with hyperlipidemia by Metformin and a traditional chinese herbal formula: a multicenter, randomized, open label clinical trial” mBio, May/June 2018, volume 9).

Naltrexone and Bupropion (Takeda, Contrave): is indicated for weight loss. BUPROPION; NALTREXONE is a combination of two drugs that helps one lose weight. The product is used with a reduced calrie diet and exericse. The product can also help in maintaining weight loss. Pateints should watch out for new or worsening depression or thoughts of suicide.

liraglutide (Novo Nordisk, Victoza): is approved in 2010 for type 2 diabetes.

Insulin: insulin or its analogs, such as insulin lispro, insulin aspart, and oral agents like glipizide, glimepride, metformin, acarbose, pioglitzone and saagliptin. In addition to these agents, a short acting insulin that can be inhaled just before nutrient intake –Exubera® –haary 2006. (Chavda, Molecules 2022, 27, 4315)s been approved by the FDA in Junuary 2006. (Chavda, Molecules 2022, 27, 4315)

–NovoLog is a modified type of medical insulin used to treat type 1 and type 2 diabetes. It is generally used by injection under the skin but may also be used by injection intoa vein. It works like human insulin by increasing the amount of glucose that itssues take in and decreasing the amount of glucose made by the liver. It is a manufactured from of human inslun where a single amino acid hs been changed (protein with aspartic acid at the B28 potion). It was approved by the FDA in 2000. In 2022, it was the 76th most commonly prescribed medication in the US. Manufacturing includes eyast, which have had the gene for insulin aspart put into their genome.

Inhbitors of sodium-glucose cotransporter 2 (SGL2):

–Empaglifloxin (Jardiance): is an antidiabetic mediciton used to improve glocuse control in people with type 2 diabetes. It is taken orally. The use of empaglifloxin has been shown to improve outcomes in epople with established CVD and it can help to slow the rate of kidney funciton decline. It is an inhibitor of the sodium glucose co-transporter-2 (SGLT02) and works by increasing sugar loss in the urine. It was developed by Boehringer Ingelheim and is co-marketed by Eli Lilly. It is on the EHO Model List of Essential Medicines

–Farxiga (Dapagliflozin): is used to treat type 2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGL2-) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion. It was developed by Bristol-Myers Squibb and AstraZeneca. It is on the WHO Model List of Essential Medicines

Organ transplantes: In the late 1990s, ressearchers first showed that pancreatic islet cells recovered form deease donors could help patients with T1D live an insulin-free existence. However, only a limited number of donor pancreases are available each year and those organs are often of variable quality. (Eli Dolgen Nature Biotechnology, 40, March 2022, pp. 291-295)

Stem Cell Protocols:

Stem cel differentiation proteocls (initially for naked administraiton together with immunosuppression)geard toward producing insulin-producing beta cells has been of intense focus given the limited availability and quality of deceased donor pancreatic islet cells. In parallel, the field has endeavored to obviate the need for immunosuppression through the use of immune privileged devices or protective materials; an approach called “islet encapsulation”. ViaCyte for example is focused on adminsitering its cells inside ouches deisgned to keep out immune cells. This encapsulation device named “Encaptra” is a pouch made of polytetrafluoethylene membranes with 0.45 um pores that is inserted into a skin flap The device relies on a well-characterized human enbryonic stem cell (hESC) line known as CyT49, The cmpany then oconverts those cells into pancreatic progenitors through a stepwise differentiation protocl. Over the course of 12 days in the laboratory, the cells progress sequentially through various stages of develoment –mesendoderm, anterio definitive endoderm, primitve gut tube, posterio foregul, before forming the pancreatic endoderm cells which go into the transplantable packets. (Eli Dolgen Nature Biotechnology, 40, March 2022, pp. 291-295)